BRIEFING REPORT
External Review Draft
ENVIRONMENTAL ASPECTS OF
VINYL/POLYVINYL CHLORIDE
NOTICE
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accuracy and po!".y it plications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
NATIONAL ENVIRONMENTAL RESEARCH CENTER
RESEARCH TRIANGLE PARK, NORTH CAROLINA 27711
October 15, 1974
l
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PREFACE
This report was prepared by a Task Force convened under the direction
of Dr. John F. Finklea, Director, National Environmental Research Center
(NERC) in June, 1974. In a preliminary assessment of the environmental
problems associated with vinyl chloride and polyvinyl chloride, an EPA
Task Force under the direction of the Office of Toxic Substances deter-
mined that emissions of vinyl chloride monomer was primarily an air
pollution problem. Accordingly, the Office of Air and Solid Waste was
given the responsibility for an in-depth evaluation of the problem. This
report was proposed as a part of this evaluation. The objective was to
review and evaluate the current knowledge of vinyl chloride and polyvinyl
chloride emissions into the environment as related to possible deleterous
effects upon human health and welfare.
The units of parts per million (ppm), in lieu of metric units, have
been used in this report to be consistent with other agencies currently
involved in the national assessment of the vinyl chloride problem.
The following members served directly on or contributed to the NERC
Task Force.
NERC/RTP
James R. Smith, Chairman Anthony V. Cclucci
Gordon Ortman
Kenneth Bridbord
J.E. Davis
Bruce Turner
Paul E. Brubaker
D. Denny
Choudari Kommineni
B. Lonneman
F.P. Scaringelli
J. Bufalini
Jean French
David Coffin
J.H.B. Garner
R. Boksleitner
Jo Cooper
OAQPS
John Crenshaw
Mike Jones
NIEHS
R. Drew
ORD, HQ
R. 'IcGaughy
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TABLE OF CONTENTS
PREFACE
1. SUMMARY, AND CONCLUSIONS
1.1 SUMMARY
1.2 CONCLUSIONS
2. INTRODUCTION
3 CHEMICAL AND PHYSICAL PROPERTIES
3.1 Physical PROPERTIES
3.2 CHEMICAL PROPERTIES
4. MEASUREMENT TECHNIQUES
4.1 ENVIRONMENTAL AIR
4.2 REFERENCES
5. ENVIRONMENTAL APPRAISAL
5.1 SOURCES
5.2 OVERVIEW OF PROCESSES
b-3 CONCENTRATIONS-
5.4 ESTIMATES OF AIR QUALITY CONCENTRATIONS
5.5 TRANSFORMATION, TRANSPORT, AND REMOVAL-
6. ENVIRONMENTAL EXPOSURE AND RECFPTOR RISK
7. UNDESIRABLE EFFECTS FROM VINYL CHLORIDE
7.1 ANIMALS
7.2 THRESHOLD LIMIT VALUES
7.3 HUMAN EFFECTS
7.4 ECOLOGY
7.5 VINYL CHLORIDE IN PERSPECTIVE
8. CONTROL TECHNOLOGY AND REMEDIAL ACTIONS'
APPENDIX A
APPENDIX B
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1. SUMMARY AND CONCLUSIONS
1.1 SUMMARY
This report represents a review and evaluation of the available current
scipnt.ific data relative to the health and welfare implications of environ-
mental pollution resulting from the production and use of vinyl chloride
and polyvinyl chloride. New information about this compound has become
available and important new data may be forthcoming in the near
future.
Vinyl chloride monomer (VCM) was first synthesized in 1837. The
vinyl chloride monomer is a synthetic chemical derived from petrochemical
feedstock and chlorine. Its principal use is in the production of a wide
variety of useful plastic materials such as floor tile, phonograph records,
pipes and electrical insulation, although it has also been used m other
ways, for example, as an aerosol propellant. The pro-
duction of vinyl chloride began in the United States in the 1930's, the first
important use was in the manufacture of synthetic rubber. Production
levels increased rapidly after World War II—the beginning of the industrial
chemical era which has produced over 20,000 new chemical products. Vinvl
chloride production in the U.S. was less than 45 million kilograms (kg) in
1943 but exceeded 2.9 billion kg in 1973. The annual growth rate in this
industry 1s expected to exceed 10 percent ner year th—ju^h th'-1 l°80's.
in the United States vinyl chloride monomer is produced at 15 plants and
polyvinyl chloride (PVC) is produced at 37 plants.
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Approximately 1500 workers are engaged in the production of vinyl
chloride, and approximately 5000 are engaged in the production of poly-
vinyl chloride. The demand for products and components manufactured from
polyvinyl chloride is extensive due to its widespread use,
i
thus the impact of control actions will be felt beyond the
VCM/PVC industry. Thousands of companies, large and small, and hundreds
of thousands of workers are engaged in the manufacture of and/or use of
plastic products made from PVC.
Only a very limited amount of VCM emission data from industrial
sources is available. VCM loss estimates of approximately 6 percent have been
reported, based primarily on materiel balance studies. Losses to the
outdoor atmospheres from industrial sources may occur at a large number
of points in the manufacturing processes and will vary depending upon the
manufacturing facility.
Currently, emissions of vinyl chloride from VCM and PVC plants are
estimated to exceed 90 million kg annually. It is estimated that 90 percent
of all vinyl chloride atmospheric emissions are believed to emanate from
nnlvvinvl chloride Dlants. Monomer plants emit less than 10 percent of the total.
Emissions of VCM from fabricating plants and from fabricated products may also
occur, but at present there are no data to Quantify what those emissions may
be. The concentration of residual monomer in PVC powder that is fabricated into
final products is an important determinant o* wrM emission*; in hnth these cases.
Fugitive emissions contribute a significant fraction to total VCM emissions, parti-
cularly in PVC plants, and these emissions are an important limiting factor
in determining the degree of emissions control that can be achieved.
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Tecnnology may currently be available to reduce vinyl chloride emissions
from VCM plants by as much as 90 percent and from PVC olants by as much as
75 percent. Control of emissions from PVC plants is a more difficult
problem which may require complex process changes. Means of controlling
emissions from PVC plants and from fabrication processes are yet to be
determined.
Polyvinyl chloride plastics usually are not readily biodegradable.
Incineration (without scrubbing) of polyvinyl chloride plastics results in the
emission of hydrogen chloride gas, but not VCM. Experimental studies indicate
that vegetational injury symptoms for ethylene and vinyl chloride are
identical; however, no known information showing vegetational damage
around VCM manufacturing or processing plants exists.
Vinyl chloride is a chlorinated olefinic hydrocarbon monomer which
is a gaS at ambient temperatures and atmospheric pressure. It is normally
shipped and stored as a liquid under pressure. It is flammable, explosive,
and only slightly soluble in water. VCM is about two times heavier than
air. Analysis of vinyl chloride usually reveals trace amounts of organic
impurities, such as acetylene, 1 ,3-butadiene, methyl chloride, vinylidine,
and vinyl acetate. Polyvinyl chloride contains residual entrapped VCM
in the parts per million range. The entrapped concentration is dependent
upon the production process and can range from 0.1 to several (5-8)
thousand ppn, which can be liberated during fabrication, particularly
wnen heated. The production of VCM/PVC involves the use of a wide variety
of chemicals other than VC.1 winch also may contribute to adverse health
effects under occupational circumstances.
LIBRARY / EPA
National Environmental Research Center
200 S V/ 35th Street
Corvalhs, Oregon 97330
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There are few data on exposure levels of vinyl chloride in ambient
air. The work place peak exposures in the past may at times have ex-
ceeded thousands of ppm; however, the average concentration would have
been less. Limited atmospheric vinyl chloride concentration measurements
have been made in the vicinity [0 to 8 kilometers (km)] of VCM/PVC pro-
duction sources. In over 90 percent of the cases the peak concentrations
have been below 1 ppm;however, one peak value (grab sample) of 33 ppm
has been observed. A few twenty-four-hour average values of 1 to 3 ppm,
at distances of 0.8 to 8 km from the source, have also been measured,
probably in the downwind plume, although over 90 percent of 24-hour
measurements were below 1 ppm.
Because of the sampling and analytical procedures used, the accuracy
of these measurements may be no better than + 100%.
Available atmospheric VCM data have been obtained using a variety
of sampling and analytical techniques with varying degrees of sensitivity
and accuracy. Consequently, the data are not directly comparable.
Standard sampling and analytical procedures have not been established
and practiced. Continuous monitoring methods suitable for field
use are not available, Measurement methodoloqy is
adequate, but has not yet been applied to the problem of atmospheric
and source sampling for VCM. The nature of VCM/PVC manufacturina
facilities,particularly the older plants, is such that
conventional source monitoring techniques may not be applicable
due to the discontinuous nature of emissions. Using an atmosoheric
/_ <-
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dispersion model, estimates of VCM concentration in a downwind plume
indicate that hourly integrated concentrations of 1 to 30 ppm might be
expected depending upon atmospheric wind and stability conditions.
The measured values and the values predicted by the model are the same
order of magnitude.
Only limited laboratory studies have been made regarding photo-
chemical reactions of VCM. Vinyl chloride does undergo atmospheric
reactions in the presence of nitrogen oxides and solar radiation; althouqh
the reaction rate is slower than with other hydrocarbons known to be in
the atmosphere. Reactions products of VCM photooxidation include CO,
formaldehyde, formic acid, formyl chloride and hydrogen chloride. In
addition, VC may indirectly contribute to the buildun of ozone. The
extent to which VCM contributes to these other components in photochemical
smog is not known. The estimated half-life of VC'1 in the atmosphere is
about 6 hours.
The principle route of human exposure to vinyl chloride is thought
to be through air inhalation, although exposure could occur from inaestion
of food and water, and from skin contact. There is no evidence to indicate
that vinyl chloride exists in normal drinking water, or in foods, except
possibly in special cases involving leaching of VCM from wrapping and
storage materials. Use of vinyl chloride as a propellant in aerosol
products has also recently been discontinued so that this source of
exposure, though significant in past years, is not anticipated to represent
a problem in the future.
Acute animal toxicity to VCM was first reported in 1938. Toxic mani-
festations in experimental animals and man included eye irritation,
increased motor activity leading to tremor and loss of muscular
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coordination, and finally narcosis, and cardiac irregularities. Exposure
concentrations in these acute studies ranged up to 400,000 ppm for
periods extending from 30 minutes to daily exposure of several hours.
Short-term acute human experiments (intermittent 5 minute exposures
separated by 6 hours over a period of 3 days) with concentrations
ranging up to 20,000 ppm produced acute toxic effects at levels above
8,000 ppm.
Chronic toxicity effects due to VCM in experimental animals include
cancer, damage to the liver, spleen, kidney, lunqs, brain and nerve
bundles. Some of the patholoqical lesions observed in these
animal experiments were similar to those later observed in humans encaged in
the production and handling of vinyl chloride.
Our present knowledge of undesirable health effects associated
with vinyl chloride exposure in man comes primarily from recent
occupational observations, complemented by additional animal data. Between 1949
and 1966 an increased incidence of excessive liver dnmane and acronst^ol^sis,
a degenerative disease affectinq bones and finqertips were reported amoriq vin^i
chloride workers in Europe. Studies in Germany revealed evidence of liver
pathology in an abnormally high percentage of PVC production workers with
a history of employment ranging from 1.5 to 21 years, but exposure levels
responsible for tnis damage are not known. Since early occupational
health studies often reported acute toxic effects, similar
to those found in the human experiments previously mentioned (dizziness,
headaches, nausea, etc.), it can be assumed that peak exposure levels of
several thousand ppm were experienced at times.
Available air monitoring data in PVC plants during the period 1950-
1959 indicates that the highest time weighted average exposures in these
facilities were in the ranqe 120-385 ppm. Studies in Europe
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and the United States since 1966 tend to confirm the earlier findings in
Europe. These studies Include observations of liver damage among workers
not directly Involved 1n the actual production of PVC. The frequency and
severity of liver pathology among PVC workers has been related to the length
of exposure; i.e. being most common 1n workers with an exposure history
in excess of 10 years. In one study, the degree of damage did not appear
to decrease with increasing intervals of time between the last exposure
and taking of biopsies.
To date 15 cases of liver angiosarcoma have been reported among workers
with a history of exposure to vinyl chloride in the United States and 10
such cases have been reported from Europe. Most, but not all, of these
reported cases have been among workers involved directly in PVC production.
Cases of liver angiosarcoma have been reported in 1 U.S. and 3 European
workers exposed to VCM, but not directly involved in PVC production.
These cases suggest that exposure to vinyl chloride at lower levels than
usually encountered in PVC production plants may be capable of causing liver
angiosarcoma. Two community cases of liver angiosarcoma have also been
reported in persons whose residences were in the vicinity of industrial
VCM emission sources, which raises the question as to whether or not
ambient air levels of VCM may, under certain circumstances, contribute
to this disease. Additional studies are, however, necessary
to confirm this possibility. Based upon the present reporting
methods, angiosarcoma is a rare form of liver cancer in the
for all practical purposes,
general population, and^is invariably fatal. The latent period for liver
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angiosarcoma has been estimated at about 20 years, based upon medical
records on occupational exposure cases. The levels and durations of
exposure necessary to induce liver angiosarcoma in the occupational or the
general population living in the vicinity of emissions sources are not
precisely known.
Compared to the general population, the relative risk of liver
angiosarcoma among workers exposed in the past to high levels of vinyl
chloride is estimated at approximately 3,000. Such a relative risk
represents a striking statistically significant difference (p <<0.01)
in the frequency of liver angiosarcoma among those exposed to high levels
of vinyl chloride compared to those in the general population not exposed
to VC, or exposed to much lower levels.
While the focus of attention has been on liver angiosarcoma, it should
be noted that a number of industrial studies indicate that the risk of
developing other cancers besides liver angiosarcoma, particularly lung and
brain cancer, is also related to exposure to vinyl chloride. The multiple
cancer risk associated with vinyl chloride also is supported by the available
animal studies.
Chronic toxic effects of VCM have been studied in a variety of animal
species. Angiosarcoma of the liver has been observed in rats, hamsters, and
studies.
mice exposed to vinyl chloride. Angiosarcoma was not observed in all animal /
In two of these, rats and mice, liver angiosarcoma has been produced by
exposures as low as 50 ppm. The frequency of liver angiosarcoma in experi-
mental animals appears to be dose-dependent above 50 ppm, but the shape of
the dose-response curve below 50 ppm is not known. Duration of exposure
has been shown to affect the tumor response in animals. Other damage,
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including tumors of the lung, spleen,and Moneys has been observed
in animals exposed to vinyl chloride,
v:m/PVC workers are exposed to a variety of chemicals which may be
carcinogens and/or liver toxins in addition to VC^- Such a complex exposure
pattern makes it difficult to draw final conclusions regarding the specific
role played by vinyl chloride in the development of liver cancer. However,
the results of animal experiments demonstrating liver angiosarcoma from
exposure to VCM in 3 species, coupled with occupational data
implies that vinyl chloride is
a causal factor in the development of liver angiosarcoma.
Although actual VCM exposure levels responsible for liver angiosarcoma
and/or other cancers in man are not precisely known, limited measurements
around VCM/PVC production facilities indicate that contiguous populations
are being exposed to low levels of vinyl chloride, which may
impose a health risk. The
presence or importance of chemical co-factors besides vinyl chloride in the
etiology of liver angiosarcoma is not well defined, though other chemicals
thorotrast and
besides VCM; i.e./arsenicals have been associated with liver angiosarcoma
in man Health implications relating to PVC dust particles containing
well
residual VCM have not been/studied.
Data in animals and man for the lower end, less than 50 'ipr, , of the
VCM dose response curve are not available. Attempts to extrapolate animal
dose response curves to define a presumed "no-effect level are fraught
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with problems which impact upon the state-of-the art in cancer research, and
the availability of resources required to conduct long time chronic stuiies.
Similarly it is difficult to extrapolate data in experimental animals
directly to man who may be more or less sensitive than animals to given che»
structures. These problems reflect important gaps in our knowledge
concerning environmentally related cancers.
The mechanism for producing liver angiosarcoma by the inhalation of
vc has been postulated but has „ot been confirmed. It is also not
known whether the mechanism can be activated by intermittent peak
exposures or whether frequent.or essentially continuous,exposure to
low concentrations is sufficient to cause cancers to develop.
1.2 CONCLUSIONS
Precise data that indicate the degree to which the general
population is exposed to vinyl chloride, and its consequent effects,
are not available. However, available data supports the following
tentative conclusions:
1. Vinyl chloride in the atmosphere in the vicinity of
emission sources is a potential health hazard.
2. Occupational cases of angiosarcoma have been observed among
PVC production workers predominantly with long-term exposure (greater
than 20 years) to VCM at unknown, but suspected high,concentrations.
However, cases of liver angiosarcoma have been reported among workers
exposed to VCM but not directly involved in PVC production, raising
the question of effects at lower levels of exposure.
3. Observations among workers and in experimental animals indicate
that there is a multiple cancer risk from exposure to vinyl chloride.
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and liver angiosarcoma and other 4p
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remain to be demonstrated as commercially visible control techniques.
14. There are no known studies of damage to veqetation in areas
surrounding VCM/PVC plants.
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2. INTRODUCTION
Historically, national and international commerce has established
markets for new products rarely with due consideration being given to
the environmental consequences of the manufacture, use, and disposal
of the new products. Consequently, air, water, soil and biota have
been contaminated with a wide variety of natural and snythetic chemical
compounds that may threaten public health and welfare. The contributory
role of a number of chemicals in the production of cancer and other
chronic degenerative disease is well known. In the absence of appro-
priate pre-market testing, assessment of environmental health hazards
for many chemical compounds often depends upon retrospective analyses
after these products have attained broad multi-media distribution.
Establishing prudent standards of environmental quality depends unon the
availability of a broad integrated data base that is sufficiently
quantitative to permit appropriate risk and benefit assessments to be
made.
Until recently, the principal environmental concerns associated
with the plastic industry has been waste-water effluents from industrial
facilities and the solid waste problems associated with accumulation and
disposal of various plastic materials.
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In 1971 the release of pbthalate plasticizers from flexible
plastic material not only aroused public health concern but served to
elicidate a mechanism of transporting potentially hazardous material
in a wide-spread fashion. More recent attention has focused upon
serious occupational health hazards associated with exposure to vinyl
chloride. The basis for this concern is evidence of vinyl chloride
carcinogenicity in experimental animals and man.
The predominate commercial importance of
vinyl chloride lies in the manufacture of polyvinyl
chloride resins which are subsequently manufactured into a large
number of useful plastic products. Vinyl chloride may
be disseminated on a broad scale as an unreacted monomer entrapped in
finished products such as polyvinyl polymers ana co-pulymerb similar
to that of the phthalate plasticizers. During the past thirty years, vi
chloride production has increased from less than 45 million kg in
1943 to more than 2.4 billion kg in 1973. Estimated loss from
industrial facilities (botli monomer and polymer production) have been
placed at over 90 million kg in 1973.
The primary purpose of this report is to provide an interpretive
and where possible, quantitative summary of available biomedical effects
of vinyl chloride. In this regard, attention is given to gaps in the
existing data base .
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Emphasis has been p-|aced upon
recent health effects developments, efforts have been made to review
and place into oerspective the older literature as well.
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3. CHEMICAL AND PHYSICAL PROPERTIES
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3.1 Physical Properties
Vinyl chloride (VC) is a chloroolefinic hydrocarbon with a density
of twice that of air having the structural formula shown below and a
molecular weight of 52.5.
H CI
NC = C
\\
Since VC boils at -13.37 C, it is a gas at normal atmospheric tem-
Derature and pressure. It melts at -160°C, and therefore is a solid only at
very low temperatures. Vinyl chloride is highly flammable having a
flash point of -108°F. The explosive limits are from 4 to 22 percent VC
in air by volume. The presence of a chlorine atom in the ethylene
molecule changes the dipole moment from 0 to 1.45 debye units. The
corresponding saturated hydrocarbon, cloroethane (ethylene chloride)
has a diDole moment of 2.05. Since vinyl chloride can be manufactured
starting with ethyleie or ethylene chloride, some of the physical
properties are changed from the parent compounds by the presence of
chlorine and the double bond. These properties and the phenomenon of
resonance reduce the reactivity of VCM. VCM is soluble ir. organic
solvents, but sparingly soluble in pure water. The quantity of
the VCM that dissolves in water will depend on the partial pressure
of the gas above the solution. VCM reacts minimally with pure
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water. If the partial pressure of the gas above the water is reduced
VCM will escape into the gas pnase. Therefore, water that contains
VCM would release the gas to the ambient air
or chemical reactions occur with water impurities which might tend
to inhibit escape of vinyl chloride. Certain salts do have the
ability to combine with VCM; soluble silver and copper
salts increase the solubility of VCM in h^O by forming complexes, for example.
Besides the previously mentioned salts, olefins will also complex with
FeCl2, Pt CI^, IrCl2, Mg^Cl2 and a host of other salts. Hence, the
residence time availability of VCM in water could be affected by the presence
of certain salts. The principal physical characteristics of vinyl chloride
are given in Table 3.1.
2-6
3.2 CHEMICAL PROPERTIES
The halogen atom attached to the carbon to carbon double bond is
generally inert. When forced to react, HC1 is extracted from VC
with the resulting formation of acetylene. Similarly, the hydrogen
atom attached to double bonded carbon atoms are highly stable in
substitution reactions. Tne order of reactivity of hydrogen atom
is allylic >3° >2° >1° >Crl^ > vinylic.
The importenc? of vinyl chloride Ires in its ability to
polymerize readily in the presence of ultraviolet light or peroxides.
The Droduct is a highly useful plastic containing the basic
structure (CH2 - CC H)n.
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The most important reactions of the olefinic hydrocarbons
are related to additions of various compounds to the double
bond, e.g., hydrogen peroxide, halogens, haloacids, halohydrins,
oxides of nitrogen, sulfuric acid and ozone. Only a few, namely,
hydrogen peroxide,dxides of nitrogen, sulfuric acid, and of couiso
ozone, should be of some impoi'tance in ambient air. The ease of
formation of free radicals of importance in photochemical
activity is ally] >3° >2° >1° > CIU > vinyl. However, the
stability of the frue radical is in the reverse order.
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Table 3.1. PHYSICAL CHARACTERISTICS OF VINYL CHLORIDEb
Formula
Molecular weight
Vapor pressure 21.1°C
Specific volume 21.1°C
Boiling point 1 atm
Freezing point 1 atm
Specific gravity, gas 15°C.,
1 atm (air = 1)
Density, liquid - 20°C
Critical temperature
Critical pressure
Critical density
Latent heat of vaporization b.p
Latent heat of fusion m.p
Specific heat
Liquid 20°C
Gas 25°C., 1 atm., Cp
Viscosity, liquid -20°C
Flammable limits in air
Autoignition temperature
Dielectric constant 17.2°C
Surface tension -20°C
Refractive index, n~^
Solubility in water 25°C, 1 atm
ch2*chci
62.50
o
34 ps ig (2.4 kg/cm gauge)
6.2 cu ft/lb (387.0 ml/g)
7,0°F (-13.9°C)
-255.5°F (-159.7°C)
2.15
0.9834
317.1°F (158.4°C)
774.7 ps ia (52.7 atm.)
(54.4 kg/cm absolute)
0.370 g/ml
79.84 cal/g
18.14 cal/g
0.38 cal/(g) (°C)
0.205 cal/(g)(°C)
0.278 centistoke (0.2734 centipoise)
4.0-22.0 percent (by volume)
881.6°F (472°C)
6.26
22.27 dynes/cm
1.4046
0.11 g 100 g water
VCM is soluble in alcohol, very soluble in ether and carbon tetrachloride.
SynOiiynis: cloroetiiene, ciiloroetiiylene
Conversion factors at 25°C and 760 mm Hg.
1 ppm = 2,56 mg/mJ
1 mg/liter = 391 ppm
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REFERENCES
1. Braker, W. and A. L. Mossman. Matheson Gas Data Book, Fifth
Edition. East Rutherford, N. J., Matheson Gas Products, 1971.
p. 561.
2. Morrison, R. T. and R. N. Boyd. Organic Chemistry, Second Edition
Boston, Allyn and Bacon Inc., 1970.
3. Fieser, L. F. and M. Fieser. Organic Chemistry, Boston,
D. C. Heath and Co., 1944.
4. Karrer, 0. Organic Chemistry, New York, Elseier Publishing Co.,
1947.
5. Porter, C. W. and Stewart, Organic Chemistry. New York,
Ginn and Co., 1943.
6. Wheland, G. W. Advanced Organic Chemistry, Chapman and Hall
Ltd., 1948.
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4. MEASUREMENT TECHNIQUES
4.1. ENVIRONMENTAL AIR
In selecting methods suitable for measuring VCM in ambient air,
two factors must be considered. The method employed must be capable
of measuring in the part per million to the part per billion range, and,
because emissions are discontinuous, the method must be capable of
responding to high concentration peaks as well as low level backgrounds.
4.1.1 Spectrophotometry
To design or describe a useful measurement technique or analytical
method for a particular purpose requires that three major criteria be
satisfied: sensitivity, accuracy and specifity. In addition practicality
and economics are important considerations in the development of new
analytical methods. As a general rule, it is most desirable to measure
a pollutant or chemical specie directly in the matrix or phase--gas, liquid
or solid--in which the material is generally encountered. This rule pre-
cludes any loss or transformation of the analyte to a non-detectable form.
Whenever possible, in the following descriptions of analytical techniques,
the above criteria will be addressed.
VCM absorbs infra red (IR) radiation in the gas phase. The absorption
bands at 941 or 917 cm 1 have been commonly used to quantify VC. However,
the method is not entirely specific for VCM as interfering substances
(Table 4.1) are encountered in ambient air.1 Multiband measurement and
data processing techniques are available to correct for these interferences,
but additional instrumentation is required. The Fourier transformation
system is an excellent example of a refinement in this technique. The
cost, however, of this type of system would be prohibitive for routine
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Table 4.1
POSSIDLE INTERFERENCES WITH VINYL CHLORIDE ANALYSIS
Corpound
Vinyl Chloride Analytical
fen"1"*
Bands
16 26
, (i JO
" 1 7
7 1 •)
Acrylor.icrnc
W
Allyl Chloride
s
V
Chlorobrononethane
w
Chloroforn
V
Ethyl one
M
s
Ethylene Dichloridc
s
Freon-11
w
! i'ricr. 12
V
S
1
Frcon-113
S
M
w
Hcthacryloni. crile
W
w
S
V
Methyl Chloroforn
s
Methyl Chloride
u
M
Methyl Met li aery late
W
w
Pcrchlotoecliylene
s
S tyrene
M
Tetrahydro: uran
M
Trichlorocchylene
M
Toluene
u
W
s
Vinyl Acetate
M
s
W
w
V in y In! luc chloride
S
V i n • 1 11': no . 1 u ot i J c
-
S
S
K i;Y :
mod
S " STRONG
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DO NOT QMCfi r,.l i,. '• t
monitoring. Infrared analyzers are not sufficiently sensitive for trace
quantities of VCM in air since effective optical paths of 20 meters are
required to achieve a lower limit of detection of 1 ppm. Accuracies of
± 10 percent are attainable when properly calibrated
with standard qas mixture. Althouqh .the technique is adaptable to continuous
monitoring, it is impractical as a multipoint detector of the type generally
required to characterize a problem area. Economics dictate this technique
for use as a research tool or as a laboratory instrument. Air samples,
either instantaneous or integrated, can be collected, concentrated if
necessary, and returned to a central "laboratory for analyses by IR.
4.1.2 Gas Chromatography
Gas chromatography (GC) is an analytical technique that separates
a complex mixture into its component parts by partitioning the chemical
material between a gas and a liquid or solid. The technique is highly
popular because of its versatility in solving analytical problems. A
wide variety of materials and conditions are available that can
be used to achieve separations effectively and inexpensively, even
2-15
^or closely related compounds.
A list of column materials that have been used to separate
vinyl chloride and related compounds is shown in Table 4.2. This by
no means is a complete list and there are other systems that can
be designed.
It is difficult to select the best column material from the
available literature, because quantitative data on column efficiencies
and height equivalent to a theoretical plate are not generally
-------
DO NOT QUQ1C Gk C
provided, nor are the objectives of the reported method always similar
to ours. Therefore, laboratory evaluation is required to ascertain
the best column material that effectively separates VCM from all
possible interferences that may be encountered in ambient air. It is
particularly important that VCM is separated from hydrocarbons and
(r)
Freons Alternatively, more specific detectors must be used in
combination with GC.
Detectors that are used in combination with GC columns are also
varied. Highly selective and highly sensitive detectors are available
which will detect quantities of material down to 10"12 grams. Completely
automated GC are commercially available for environmental monitoring.
On some of these instruments all that needs to be changed are the column
materials and operational parameters. However, with rare exceptions,
measurements are not made continuously but are made by taking instan-
taneous samples at short periodic intervals.
4.1.2.1 Detect6rs--The flame ionization detector (FID) is a general
purpose detector which responds to most organic compounds, has a wide
linear range of several orders of magnitude, and sensitivity down to
parts per billion. The response to a chemical compound generally varies
with the number of carbon atoms. However, certain carbon atoms have
reduced or no response when the carbon atom is attached to atoms other
than hydrogen; e.g., CI, 0,S. The detector is insensitive to almost
all organic gases and compounds. The minimum detectable concentration
for VCM using a 10 ml sample of gas is 0.01 ppm. When coupled to a GC
column to achieve separation, the FID has been the detector of choice
because of its sensitivity and minimal cost for the analysis of complex
(R) Trademark - E.T. duPont de Nemours & Co., Inc.
-------
LT.-'M" f
zz :.r O'jlie or cite
organic mixtures. The combination of QC-FID has been used under field
conditions, but power requirements and the need for hydrogen gas reduce
the practicality of the instruments for routine monitoring.
The thermal conductivity detection (TC) is mentioned only for
historical purposes. The detector measures changes in heat capacity of
the carrier gas, usually nelium or hydrogen, when materials elute from
the column. The sensitivity is low when compared to other available
detectors. It is not suitable for trace analysis. In addition, TC
responds to water vapor; this causes problems in identifying and measuring
compounds of interest.
A third group of detectors fall under the general classification of
D.C. ion chambers. These include argon ionization, helium ionization,
micro-cross section detectors and, most important of all, electron capture
detectors. The argon detector consists of 2 or 3 parallel, electrodes
90
and a radioactive source, usually Sr , which excites the argon carrier
gas. When chemical compounds elute from the column they are ionized by
the excited argon. Under a voltage gradient up to 1,000 V these ions
produce an increase in current flow across the plates or electrodes
which is proportional to the concentration of the eluting material. The
sensitivity is food, but it is non-specific and temperamental.
The design of the helium detector is similar to the argon detector,
except that helium is used as the carrier gas. Voltage gradients as high
as 2,000 V can be applied across the plates. Radioactive hydrogen, tritium,
is frequently used as the excitation source. This detector is also
temperamental, highly sensitive and non-specific, but is usually recom-
mended for traces of inorganic gases to be detected with gas-solid
-------
r> r- \ r r
haft
p - *. /• t- t j *¦ , *¦ ^ r1 ^ r
chromatography. 1:,.' !.^i ^ >
The electron capture (EC) detector is of similar design as the other
DC-ion chambers. Nitrogen or argon is used as the carrier gas and
63
tritium or Ni as the radioactive sources. Low voltages 5 to 25 volts
are applied across the plates usually in a pulsating mode to eliminate
polarization of the electrodes. The detector is specific and highly
sensitive to halogenated materials and other materials that absorb
electrons. It has a smaller dynamic range and is more temperamental than
the FID. Sensitivities for VCM have been reported to be less than that
with the FID because of the presence of a single chlorine atom in the
4 24 ?a
molecule. ' More recent data indicates sensitivities tabulated
in Table 4.3.
Table 4.3 SENSITIVITY OF SELECTED
DETECTOR USED IN GAS CHROMOTOGRAPHY
TC
Argon D
FID
EC
Vinyl chloride
2 x 10~6 g
1.9 x 10~9g
2.2 x 10"9 g
2.3 x 10"9 g
Trichloroethylene
2.2 x 10~6g
1.0 x 10~8g
8.5 x 10~9 g
2.0 x 1011 g
The GC-EC has the advantage of requiring only one gas cylinder of
nitrogen, and, because of its specificity, complete resolution of VCM
by the GC column is no longer mandatory. Battery operated GC-EC instruments
have been manufactured commercially.
The micro coulometer is a highly sensitive and electrochemical detector
of the chloride ion. The specificity of this detector is increased when
used with gas chromatography. Chlorinated hydrocarbons, such as VCM are
pyrolyzed as they elute from the column to form gaseous HCI which reacts
-------
Do mj cj:e
regenerates Ag+ until the electrical balance is restored. The detector
will also respond to any substance which precipitates Aq. However, dependinq
on column and pyrolysis conditions, these potential interferences can be
eliminated. With electrochemical efficiency of close to 100 percent, the
coulombs generated to restore the
balance is proportional to the quantity of Cl~ in accordance with
Faraday's law. The detector is highly accurate because the
coulomb is a primary standard, and hence standard reference materials
are not absolutely essential. The sensitivity of the detector for VCM
is of tne order of a few nanograms. Power requirements make
this system impractical for field instrument use, but it is excellent
in the laboratory technique.
Another electrochemical detector is the conductivity device
28,29
developed by Coulson for use with gas chromatography. The
conductivity detector measures water soluble ions or gases that
produce soluble ions when they react with water. The effluent
material is either oxidized or reduced in a small furnace prior to
reaching the detector. Depending on the mode of operation, the
detector response can be restricted to HC1, SO2 or SO^.
High sensitivity is attainable because of the solubility of these
gases in water and the high mobility of the hydrogen ion produced.
Sensitivity of the order of a few nanograms is possible. The ultimate
sensitivity depends on the geometry or the cell constant. More recently
the conductivity cell has beun designed by Hall to yield nigher sensitivities
30
than the Coulson detector. Again, specific detectors reduce the demand on
the column to resolve compounds with elution times close to VCM. Power
requirements reduce the practicality of this detector under field
-------
p. D * *~T
1 ' ! 1
nn iv "¦' »*!' W'Tr -¦ • -
conditions. ^ ^
The Beilstein test is a classical flame test for detecting halogens
in the presence of copper. This test is the principle for a flame photo-
metric detector that has h
-------
DRAFT
DO fiOT QUOTE 03 CITE
of each other. The necessity of one or more gas cylinders and power
requirements limit their utility in the field instrument.
Some techniques are more selective than others, some are too expen-
sive for field application and some require more extensive evaluation
for the purpose of measuring VCM.
4.1.3 Other Methods of Analysis
Coulometry has been used to measure olefinic hydrocarbon by reaction
with electrogenerated Br,,. This technique is not useful for measuring
VCM in ambient air because of the long reaction time required for the
brommation of olefins. In addition, reducing substances such as SC>2 would
interfere by consuming bromine. Oxidant would cause a negative
22,23
interference. Wet chemical methods have also been developed based
on the bromination of VCM.. then titratinq excess bromine. The sensitivity
is only 0.1 mq. Olefins, aromatic compounds t^at readily add firc"iinc? aid
and reducinq agents interfere with this wet chemical method.
Vinyl chloride in air has been analyzed colorimetrically by
29
collection on activated carbon. The VLM was extracted and oxidized to
formaldehyde. The formaldehyde was determined in the usual manner by
reacting with chronotropic acid, however, ethylene and methanol interfere.
Sensitivity is only a few micrograms.
?0 21
Polaroqraphy 4 has been used to measure VCM by bromination at the
dropping mercury electrode. When this procedure was applied to
volatile VCM from plastics, it gave higher result than the analysis
of total chloride. Hence interfering volatile materials are present.
Sensitivity for VCM was onlv 70 ng/ml.
-------
DRAFT
DO NOT QUOTE Ok CITE
4.1.4 Sampling and Laboratory Analyses
The most inexpensive approach to monitoring VCM would be to collect
samples in a suitable manner and return them to a central laboratory
for analysis. Using this approach, samples could be collected through-
out a suspected problem area with a minimum of power, a minimum of
equipment, and with unskilled personnel. Grab samples are collected,
23
as described in the interim procedure in Tedlar bags or stainless
steel ca listers. Varying degrees of instability from 0 to 10 percent
per day have been reported when VCM in air was stored in Tedlar bags.
It is possible leaky bags are responsible for losses. However, VCM in
pure air appears to be stable. In polluted air, particularly in the
presence of ozone, reactions are expected to continue. Direct photo-
excitation of VCM are not expected to occur because solar radiation
below 290 nm does not reach the lower atmosphere. Hence, this solar
energy is not absorbed by VCM in ambient air. However, in the presence
of nitrogen dioxide which absorbs solar radiation about 2900 nm,
secondary reactions involving ozone (produced by the photolysis of NO2)
and VCM occur. It may be possible to spike the air sample with a free
radical or ozone scavenger to stabilize the VCM in the sample. Tedlar
bags used for sampling create a storage and handling problem. Wall losses
and permeability of the VCM through the walls of the plastic bag do not
appear to be a problem with Tedlar at concentrations in the range of
10 ppm.
-------
p ^ n*^
[Ci fiOi 0R ^
Evacuated stainless steel canisters have the advantages of
being more rugged, and more easily stored and transnorfpd than
Tedlar bags. These canisters need only a silicone septum through
which a needle can be inserted to evacuate the system to a low
pressure. The needle is withdrawn and the septum seals itself
maintaining a vacuum until a sample is ready to be taken. At the
sampling site, a needle is again inserted and polluted air allowed
to fill the canister. The needle is withdrawn and the
septum seals itself again. At the laboratory, an aliquot of the
sample is removed with a gas tight syringe and injected directly
into a gas chromatograph or other measuring device.
The above procedure yields a short term concentration
and does not yield a total dosage It
appears necessary - particularly because of the discontinuous
nature of the emissions that produce pockets of hiqh concentration of
VCM— that some accurate measure of the total or average dosage
over a prescribed period be obtained.
4.1.5 Liquid Scrubbers
Very little information is available concerning the use of liquid
scrubbers for the collection of VCM. The physical properties of VCM
are such that it is not easily trapped by liquid unless some
complexation reactions can be produced. Certain salts have been
reported to complex VCM, but these salts have not been thoroughly
investigated for this purpose. In addition, liquid scrubbers for
monitoring air pollutants, introduce collection, handling and stability
problems that render the technique impractical.
-------
4.1.6 Solid Scrubbers
Solid scrubbers
fiOl ooo^t o
arc more easily handled,
transported and have fewer collection problems. Activated
charcoal has been extremely useful for the collection of gases
and vapors including VCM. The capacity of charcoal for VCM is
11 in i tod.
Hence, problems have been reDnrt.pH resulting
from the use of small tubes and large sampling volumes. It is
imperative that all newly purchased charcoal be reactivated under
nitrogen to maintain its absorption capacity and to remove
impuities thai may interfere in i/ne analyses. Charcoal was
selected as the collection medium in the interim procedure in order to
to obtain time weighted averages. The use of multiple sections
was specified to ascertain the quantity of charcoal required under
field conditions. It is not yet known how the procedure will respond
under field conditions and relative humidities close to 100 percent to
determine the quantitv of cnarcoal required to collect VCM uniter the
most adverse conditions. Other solid scrubbers may be more suitable for
collection of VCM.
3
Mollis reported long retention times of low molecular weight
hydi oc.i rbons and halogenated hyd) ocarbons on porous polyaromatic
32
polyncr beads. Williams and Uinstead dctci mii nod a number of
haloqenated hydrocarbons by concentrating the sample on Parapak Q & S.
-------
pp T
DO '"x'^
Ihc materials \scrc thermally desorhcd .it 100 °C for analysis.
Thc> used the micro couloincter \%ith the silver cell to determine
25
VLM at the 10 parts per billion level. Lonneman used enrbowax
under erogenic conditions to concentrate the sample and analyze
concontr.it ions of 100 parts per trillion by gas chromatography.
26
More recently, Hollar successfully concentrated VCM from aqueous
solution by adsorbing on carbonsicvc B. Quantitative recoveries
were obtained from aqueous solution containing from 5 ng to 5
Jig ofvCM. All solid scrubbers should be evaluated under sim-
33
ulated field conditions. Permeation devices are available commerically
which will generate low levels of VLM -jn air and the resultina
mixture diluted with humid air. In this manner, collection and
rfirimnns c.tn hr more definitively established. The
stability of VCM on storaqe in tne presence 0f reactive pollutantsin the
atmosphere is not known. Some investigators have reported that
VC might be polymerizing on these scrubbers. It has been
27
demonstrated by Lajos and P.ululy that hydroquinone improved
recoveries of VCM from charcoal without reducing its adsorption capacity.
4.1.7 Sample Preparation
Grab samples present no problems :ince
aliquots ate injected directly into a gas chromatograph, if the
range of interest is greater than 0.02 ppm. Air samples can be
concentrated as previously described, to detect levels of 0.2 ppb^
if a sufficient sample is avail^le. (toed recoveries from charco.i L
h ive been iepoi1ed by Broun bv exti acting with (\S,. This is an
-------
DRAFT
iiH WO I Qlluf,: C- CITE.
excellant solvent for gas chromatography when using the FID This detector
gives no response to CS under the usual operating condition and solvent
interferences are eliminated. KeenmanJ however, observed that appreciable
quantities of VCM evaporated into the head space above the liquid when CS^
was used as the extractant for VCM. Total recovery of VCM in both the liquid
and the gas phase was only 80%. When VCM was extracted with tetrahydrofuran
(THF), he obtained a recovery of 88 percent with less diffusing into the head
space than was evident with CS2»
4.1.8 Automated Monitoring
Completely automated monitoring
instruments, which arc commercially available, can be easily
modified to measure vinyl chloride. For example, the carbon
monoxide - methane nnuiyzer, which ubtb a pi ecolunui, u.i I a and defining the magnitude of the problem, however.
-------
DO NOT QUOTE. OR CUE
wo11 defined studies should be undertaken to eliminate sources
errors and refine the procedures prior to standardization.
-------
nn.
4.2 REFERENCES
DO NOT QUOTE OR CITE
Keenan, R. R. Private Communication. G. D. Clayton Assoc. Southfield, Mich.1974.
Vvakhirev, D.A. Smolyan, L. E. Reshetnikova, N. D. Demina,
M. I. Vlasova, and A. A. Karnishin. Analysis of Vinyl Chloride
by Gas-Liquid Chromatography'- Jr. Pa. Khim, i Khim. Tekhnol. £: 490-497, 1962.
3. Hollis, 0.L and W. V. Hayes. Gas-Liquid Chromatographic Analysis of
Chlorinated Hydrocarbons with Capillary Columns and Ionization Detectors.
Anal. Chem. 34:1223-1226, 1962.
4. Clemons, C.A. and A. P. Altshuller. Responses of Electron Capture
Detector to Halogenated Substances Anal. Chem. 38^(1); 133-136, 1966.
5. Martur, V.G. S. A. Antipova, and V. S. Kozlova. Analysis of Mixtures of
Fluoro and Chloro Derivatives of Elhane and Ethylene on the KhL-3 Laboratory
Chromatography. Ukr. Khim. Zh. 32(4):391-392, 1966.
6. Hindshaw, L.D. Gas-Chromatographic Determination of Chlorinated
Hydrocarbons in 1,2-dichloroethane - J. Gas Chromatog. 4_(8): 300-302, 1966.
7. Esposito, G.G. and M. H. Swann. Identification of Aerosol ProDellants
in Paint Products by Gas Chromatography. J. Paint Technol. 39(509):338 -340,
1967 .
8. Koenig, H. Separation, Detection, and Quantitative Determination of
Aerosol Propellants by Gas Chromatography. Fresenius Z. Anal.
Chem. 232(6):427-432, 1967.
9. Balandina, L.A. and A. I. Subbotin. Chromatographic Analysis of Products
of the High-temperature Chlorination of Ethylene- Zavod. Lab. 34(2): 154 1968 •
10. Popova, T. P., Kevyagina, K.I. Kevyagina and M.A. Mamedov. Gas-chroma-
tographic Analysis of a Vinyl Chloride Mixture. Aserb. Khim.
Zh. No. 5, 116-120, 1967 .
-------
DRAFT
DO NOT QUO:;! Oil CITE
11. Maltese, P., A. Mori, and S. Panizzi. Gas-chromatographic
Determination of Vinyl Chloride in Hydrochloric Acid. Chim.
Ind. (Milan) 50(6):667-668, 1968.
12. Foris, A., J.G. Lehman. Gas Chromatographic Separation of Halo-
carbons on Porapak Q Porous Polymer Beads. Separ. Sci. 4(3):
225-241, 1960.
13. Karabanov, N.T., L.V. Isaicheva. Chromatographic Analysis of Vinyl
Chloride. Gasov. Khromategr. No. 12, 82-87, 1970.
14. Vlasov, S.M., G.N. Bodyagin. Gas Chromatographic Analysis of
Trichloroethylene. Tr. Khim. Khim. Tekhnol. 1_: 161-162, 1970.
15. Zalinyan, V.P., N.B. Znamenskaya. Chromatographic Analysis of
Gas Mixtures in Vinyl Cnloride Production. Khim. Prom. Tsvet.
Metal. No. 45, 24-30, 1971.
16. Newman, M.S. et al. J. Org. Chem. 28:1851, 1963.
17. Smith, B. Acta Chem. Scand. T6:351, 1962.
18. Levadie, B. Amer. Ind. Hyg. Ass. J. 21_:20, 1960.
19. Hannon, C.I. et al. J. Gas Chromatog. 1:27, 1963.
20. Ryabov, A.V., and G.D. Panova. Application of the Polaroqraphic
Method in Analysis of Unsaturated Organic Compounds. Doklady Akad.
Nauk.(S.S.S.R.), 99:547-^49, 1954.
21. Meshkova, O.V., V.fl. Dmitrieva, V.D. Bezuglyi. Polarographic
Analysis of Waste Waters from Poly-(vinyl chloride) Production. Khim.
Prom. (Moscow). £7(4): 271-273, 1971.
22. Tsendrovskaya, V.A., K.I. Stankevich, I.S. Reisig. Selection of
a Method for Determining Volatile Substances Separated from Some
Plastics. Primen. Polim. Mater. Izdelii Nikh. No. 1, 418-A25, 1969.
-------
DRAFT
i::j NOT P'JOi L cr; CITE
23. Brown, D. EAP Region IV, Athens, Ga., 1974. Personal Communication
with QAEML, NERC, RTP, N.C.
24. Boettner, E.A. and F.C. Dallos. Capture Detection of Chlorine and
Lead Substituted Compounds. J. Gas Chromatog. 1965.
25. Lonneman, W.A. Measurements of Vinyl Chloride from Aerosol Sprays.
CPA-NERC, Researcii Triangle Park, N.C., Unpublished, Apr., 1974.
26. Bellar, T. national Institute of Occupational Health, Cincinnati,
Ohio. Personal Communication with B.W. Gay, CPL, NERC, Research
Triangle Park, ii.C.
37. Lajos and Raduly - Chemical Abstracts. 76:36690i, 1972.
28. Coulson, D.M. Colormetric Determination of Vinyl Chloride in Air.
J. Gas Chromatog. 4:285, 1966.
29. Gronsberg, E.S. Khim. Prom 1_:30-31 , 1966.
30. Hall, R.C. A Highly Sensitive and Selective Microelectrolytic
Conductivity Detector for Gas Chromatography. J. Gas Chromatog. 12(3)
1974.
31. Bowman, M.C. and M.J. Beroza. J. Gas Chromatog. 9/44)., 1971.
32. Williams, F.W. and M.E. Umstead. Determination of Trace Contaminants
in Air by Concentration on Porous Polymer Beada. Anal. Chem. 40:2232,
1963.
33. O'Keeffe, A.E. and G.C. Ortman. Primary Standards for Trace Gas
Analysis. Anal. Chem. 38(6):760-763, 1966.
-------
Dr) * t~ -r
K'-.r i
"1 « . -
' ¦ " " rr
v J ^ » w I * L
5. ENVIRONMENTAL APPRAISAL
13.1 SOURCES
Current monomer processes are of four types:
1. acetylene plus hydrogen chloride;
2. direct chlorination of ethylene and dehydrochlorination;
3. balanced direct and oxychlorination of ethylene and dehydrochlori-
nation,
4. oxychloriantion using oxygen instead of air, Current polymer
processes are categorized as: suspension, emulsion, bulk, and
solution. Thus eight basic processes are discussed.
This review is limited to existing commercial processes in the United
States. There are two general methods for the production of vinyl chloride
monomer. Tiiese are the acetylene hydrogen chloride reaction:
iic = cii + ;ic,i —> n c =- aici
.mci t lie Liicriin I uuivdrc chl o t j ,;n t. ion oT ] , 2-dicli ] orc>cthnnc :
CJCII, - CIL/'J > 11 c - VAC1 - HCl
Vinyl chloride monomer (VCM) plants are integrated with an ethylene
dichloride production unit in the second procedure. The overall processes
differ primarily in the manner in which the ethylene dichloride is produced.
¦c '
-------
Nine producers operate a balanced plant in which ethylene is
chlorinated by a mixture of hydrogen chloride (HC1) and air to produce
ethylene dichloride. Part of the HCI used for this process is in the form
of recycled products from tne thermal dehydrochlorination of ethylene
dichloride as shown above.
Three producers use an integrated process in which the ethylene
dichloride is produced by the direct chlorination of ethylene. Hydrogen
chloride is recovered from the dehydrochlorination step, but is not re-
cycled into the process.
One producer use- the balanced oxychlorination process with the
exception that oxygen is used for the oxvchlorination reaction sequence.
Two companies use acetylene as the starting material.
Polyvinyl chloride (PVC) is produced at thirty-seven sites at a
total yearly rate of approximately 2.4 billion kg. There are four
processes used to manufacture PVC:
1. suspension polymerization (78 percent of total production);
2. emulsion polymerization (12 percent of total production),
3. bulk polymerization (6 percent of total production); and
4. solution (4 percent of total production).
Emissions of gaseous vinyl chloride monomer (VCM) are known to
occur at both VCM and PVC resin plants. This VCM is distributed into
the atmosphere surrounding the emissions source in patterns that depend
on the amount of VCM released, the nature of the plant area from which it
is released, and meteorological conditions. VCM air concentrations
which may occur as a result of such releases are of interest.
-------
DRAFT
00 NOT Ok CUT
Data accumulated for this study show that annual production
capacities are 2.42 billion kg of VCM and 2.15 billion kg of PVC resin
(Table 5.1). Manufacturers operated at full capacity in 1974.
On the basis of the analysis of the VCM emission data so far supplied
to EPA by VCM and PVC producers, total VCM escaping to the atmosphere
is on the order of 95 million kg per year. However, approximately 90
percent of the total VCM emitted comes from PVC polymer production
facilities. This is shown in Table 5.1.
Table 5.1. U.S. VINYL CHLORIDE MONOMER AND
POLYMER PRODUCTION AND EMISSIONS (1973)
Plant
type
Production
Kq X 106/yr
VCM Emi tted
Kq X 106/yr
VCM Emi tted
Percent of production
VCM
2432
6-7
0.2 - 0.4
PVC
2159
65-86
3 - 4
It is also important to note that while monomer plants emit less
VCM per kq of product than polymer plants, this may partially be
offset by the tendency for monomer plants to have larger pro-
duction capacities than polymer plants. The net result is that the
absolute VCM emissions levels from polymer plants are usually in the
range of 2 to 5 times those of monomer plants.
-------
r>;v \ry
r: !i;." (;:?!' o.i cut
Two additional features of the industry are significant in terms
of potential VCM concentration levels in the atmosphere near plants.
VCM plants are clustered primarily in areas
along the Texas and Louisiana Gulf coast, and PVC plants tend to
be located close to/or even adjacent to the VCM production site.
This "clustering" of plants is greatest on the Gulf coast in the
Pasadena-Deer Park, Texas region and in the Baton Rouge, Louisiana
area.
VCM monomer producing companies are listed in Table 5.?.1.Included
in this table are the companies and their geographical locations,
population figures for adjacent communities and calculated VCM emissions
levels. PVC polymer producers are similarly listed in Table 5 2.2.Table
5.2.1 shows the location of geographical clusters of VCM and PVC plants.
-------
5.2 OVERVIEW OF PROCESSES
Ihe follo^vn^ tabulation oL producers of vinyl chlorjdc monomer indicates
puSlislied projection capacity and wn\l chJoiide emissions t»y process and Jocation.
(Table 5.2.1 through 5.2.3)
r>r) i\
FT
Table 5 . 2. 1v:v.omlr hast i mission data
DO
11
lUOTE OR C
CI tv
CeT.jl l'l V_
Allied Chenical
Amu 1ican Chcra.
Continental Oil
Itou Chtmcal
E tIi> 1 Corp .
B.F. Goodrich
Kouochcm, Inc.
P.P.C. Industries
H
Shell Chetnical
II
Tcnncco Chen.
' iT • I lO.l
IYyu 1 J L in.
Prod.ic t ion
I inn
K n 1 ¦> s 1 r. s
Tvpe
Pr-. ¦
TOTALS
1 Ito'i Rouge, La.
Long Beach, Ca.
I .Ae Charle;,, I.i
Freeport, Tex
Plaquemine, la. \
Oyster Cruel , Tc^j
Baton Kou^e, La.
Pasadena, lex.
Cilvcrt City, ky .
C? israar, I a .
I ike Charles, Ln.
Cuayanl1]a, P.R.
Deer Park, lex.
Narco, la
Fabidcna, lex
165,963 C
358,613 c
77,998
11.997 f
7,739 c
f
165,96 J c
89,277 ''
31,627 j
7,739
77.998
12,773 h
89,27/ h
kgxlOu/yr 1kgxlO /yr
136 1 0.4
77
273
82
155
364
123
68
455
136
136
261
398
318
114
0.2
i 0.8
¦ 0.2
0.5
. 1.1
, 0.4
I
: 0.2
1.4
' 0.4
1 0.4
• 0.8
1.2
0.9
0.4
1,096,984 , ' 3096
9.3
B d
B
B
DC
DC
B
B
DC 1
B
A k
B
B
B
A
(a) 1970 Census uiti
i \ ) - 25,225
(h) tlirris Coei:\ - l,7-],a12
(i) Dmcl liKm . >tiiM (iM)
(j) Pupu la; i,in . u l :or h, (•>
t. f ... * i ) i¦ l \ t
-------
Table 5.2".J.PVC POLYMER
Ccv pany
Plastics Division
Air Products § Chem., Inc.
American Chem. Corp.
(Joint Venture-Altlantic Rich-
field Co. § Staurfer Chem. Co.)
Borden Chem. division
Borden, Inc.
Conoco Plastics Division
Continental Oil Co.
Diamond Shamrock Chemical Co.
(Subsidiary Plastics Div.)
Diamond Shamrock Corp.
(Industrial Chemical Div.)
Ethyl Corp.
Chem./Plastics Division
The Firestone Tire £ Rubber Co.
Chemical/Plastics Division
The General Tire 6 Rubber Co.
B.F. Goodrick Chemical Co.
The B.F. Goodrich Co.
Location
Calvert City, Ky.
Pcns.icola, Ela.
Long Beach, Ca.
IJ li.opo Lis;, III.
Lcc.mns Lor , I'.rzs .
Aberdecn , Miss.
OL I jhtr.ia City, O'cla.
')c !.. .v re Ci^y, Dcla.
Deer Park, lex.
Baton Rouge, La.
Perryvi]le, Md.
Potts to^ n , Pa.
Ash 'hi] a, Ohio
Long Heach, Ca.
Henly, 111.
Louisville, Ky.
Av-on L^\c, Ohio
?eJrjLc\to. n , X.J,
VCM EMISSIONS DATA
CiLV
copulation
31,627
59 ..50 7
358,633
1 ,122
32,9..;
6,157
36 6,-'.31
2 ,024
12,773
165,963
2,091
25,355
24,313
358,633
2,610
361,472
12 ,261
Tyoc of b
p>~ o c n r
Suspension
Suspension
Srspension &
Emulsion
Suspension &
Ei-u 1 si on
S1.. i/i'iioion &
Ei lul'jici
Suspension &
I>. i']: O'l
Susrn. ns :on,
EnuJ'.jon a
Solution
Suspension,
Emulsion,
Bulk 2"'
£. Sclrtion 10
PVC capacity
kg x 10°/vr
59
23
57
129
100
36
113*
82
59
64
15
57
57
125
57
59
O
CD
CD
—-t
/3
a
CD
1
r-n
VCM
c
emissions
kg X 10"/vr
2.2
0.9
2.3
5.2
4.0
1.5
4.5*
3.3
1.9
rji 2-5
3b 6-8
2.3
2.3
5.0
2.3
2.4
i
f
-------
DRAFT
-EILMOT QUOTE OR CITE
Teble 5.2.2 (Continued)
C'irM.inv
"h^ncal Division
The Cioodyear Tire 5 Rubber Co.
Great American Chemical Corp.
Keysor-Century Corp.
Monsanto Polymers 5 Petro-
chemicals Company
Monsanto Company
National Starch fT Chemical Corp,
Hooker Chemical Corp.
(Subsidiary Ruco Div.)
Occidental Petroleum Corp
Thompson Plastics Co. Div.
01in Corp.
Pantasoto Co.
Robintech, Inc.
Plastics Division
Stauffer Chemical Co.
Tenneco Plastics Division
Tenneco Chemicals, Jnc.
Chemicals 5 Plastic Div.
Union Carbide Corp.
Location
Pl.iqueininc, La.
Nijgra Tails, N.Y.
Fit chburg, Mass.
Snugus, Ca.
Springfield, Mass.
Mcrcdosia, 111.
Burl my Ion, N.J.
llicl.svil le, N.Y.
As sonet, Mass.
Poss.ii c , N.J.
Poj.it I'lo.i^ant, W.Va.
Painsvilie, Ohio
Dol.vj.iro City, Dela.
Burlington, N.J.
rienunp, ton, N.J.
l'.is.ulon r>, Tex.is
Tov.Ci.Lv, To.:.
So. Charleston, W.Va.
CiL>
popu ' ti o.i
7 ,739
85,615
A3,343
163,905
1 ,17S
1] ,991
48,075
55,124
6,122
16,536
2 ,02 4
11,991
3,917
89,277
3 S, 9 0 o
16 ,333
ly^o oC
O '-nc S
[ "iu I •• i cm &
Lull. 35
Si:'.,)' .ij on
Si'-.pen ,: on
Sinpcns ion
& r.: HI 1m on
Cmuls .on
Su'.pons ion
& i'.ulU 70
Suspension
Fi-.'il si on
Suspension
Susru rsion
Suspension &
Enml .s ion
SuspcP'. i on L
Solution 50
VCM d
PVC c vaci ry e
kg X 106/vr ks x 106/vr
45
45
18
16
68
82
5
68
120*
113
73
75
o
CJ
c
c:
n~
27 O
136
91
54
r 11
1.8
1.8
0.7
0.6
2.7
0.2
3.3
0.2
2.7
2.2*
4.5
J 2.9
J
1.1
5.4
3 6
2.2
-------
Table 5.2.2 continued
DRAFT
Con'jrny
Location
City
a
Pouiction
"-k Qv'Ote
1ypc of
b
Prorc'-.s ^
CP CITE
?VC c. L-nty
kg X 106/yr
7( ;
c
kg X 10^/yr
Uniroyal Chemicals, Inc.
Uniroyal, Inc.
Painsville, Ohio
16,536
Suspension
I L-.ulsior.
Sub total
14
3,156
2.5
86.3
U.nr_,v CO'. STRUCT ION
Certcxnued Corp.
Lake Charles, La.
77 ,978
(i:nr;:.o.uO
90
4
Georgia Pacific
Plaquemine, La.
7,739
1!
90
4
Sh ml'.ca
1
Oyster Creek, Tex.
11,997
11
Sub Lotal
TOTAL
110
290
2,446
5
13
99
Footnotes
^Population given is for Paducah, Ky.
eLo'? A-i^olcs County - 7,032,075
O
O
o
1970 Census Data . Office Air Quality Programs' computer file. 1
O S2
Who statement.- on type of process is a preliminary one. Numbers in parenthesis indicate d
cMi:naled production by that process in millions of pounds per year. ^
Ci'.\ i r.ipo ] aire! figures in millions of kg per year (industry total 100 million kg/yr) 0
nascl <>n c-s, L m.a Led emission of 4.0 percent VC 'A durinc pol>mer production and recovery.
O
m
-------
labie 5.1.2 continuea
Jr^U'nolcs
f
To la I for two plants
^Oklahoma County - 526,805
:l.irrxs County - 1,741,912
1rijton Kou^c Parrjsh (County) - 302,031
Henry County - 53,217
k
ri^quc-i ities Parrish (County) - 25,225
1
Burlington County - 323,132
/O o
o S!
o
so
cn
m
-------
luble 5.2.3
CLUSTERS 01- VINYL CHLORIDE EMISSIONS
to Not ^AfT
T'r*
¦>
C'oiiiP 1 v
Li >ca t i on
City
populat:
a 1
on
Ja pac i [ \ 1
b
.miss j o us
Typc~
prot i';V.
kg X l(J^/yr
kg X lU6/yr
A11j cd ( li- ..ical
'in tun Roup,o, I.a .
165,963
c
136
0.4
B d
Dow
PIaquem ] ne , la.
7,739
f
154
0.5
DC
TUiy] Corji.
Baton Rou,"r, La.
165,963
c
122
0.4
B
r L h >1 Corp.
(1 nt1 us Li j >i 1 Choni.
Div . )
Baton Rouge, l.a.
165,963
c
82
3.3
Susponsion
Georgia Pacific
(uiK'or construction
Plaqueraine, l.a.
)
7,739
f
91
3.6
Unknown
The GooJ^ear Tjro
& Rubber Co.
(Chcrni C.i l 1)1 v .)
1'Jnquomine, l.a.
7,739
f
45
1.8
Subpursio"
Monochcn, 1 .
Gojsraar, La.
7,739
f
136
0.4
A k
Area emissions
•
10.4
Continental Oil
Lake Charles, La.
77,998
272
0.8
B
1' . 1J . G . J ndus Lries
Lake Charles, La.
77,998
136
0.4
B
Shell ChcmicaL
Xarco, La.
38
0.9
B
Certaint cofl Corp.
(under construction
Lake Charles, La.
)
77,998
91
3.6
(unknot mi)
Area einLssionb
5.7
Djanioncl Sha.-irock
Corp ., Di 1 umd
Shamrock C'mti.
Co . (Su ary
Plastus Div.)
Deer Park, Tex.
12,773
8
113
9.5
Suspend Loa
& r.nm 1 s i on
I thy] Cot p.
f1 i -.adena , to %.
89,277
> - i'
r;
68
0.2
DC
-------
T.ible 5.2.3 (CONTINUED!
**as.w
Company
1
Location
City
population
Capacity
kS X 106/yr
b
Emissions
kg X 106/yr
1
1 1">V«
process^
Shell Chemical
Deer Park, Tex.
12,773 8
397
1.2
B
Tenncco Chem.
Pasadena, Tex.
89,277 8
113
0.&
A J
Union Cat bide
Corp . , Cite 'ii ca Ls
& Plastics Div.
Texas City, Tex.
38,908
91
3.6
Suspi r. -
Area emissions
9.9
Dow Chemical
Freeport, Tex.
11,997 e
82
0.2
DC
Dow
Oyster Creek, Tex.
11,997 °
363
1.1
B
Shin tech
Oyster Creek, Tex.
11,997 C
113
4.5
Unknown
Area emissions
J
b .y
(a) 1970 Census data
(b) Extrapolated figures based on estimated atmospheric emission loss of 0.3 per cenL
of VCM produced in monomer plants
Extrapolated figures in millions of kjj per year (industry total 100 million ki>/yr
Yr ) based on estjr'ated emission of 4.0 percent VCM during polymer production
and recovery.
(c) Baton Rouge Parrjsh (County) - 302,031
(d) Balanced (B) - combination of direct chlorination and oxyclil or j nation process in
which the hydrogen chloride produced in cracking is recycled to the o>;yChic,r.nilr- -
process.
(e) Bra-ona County - 108,312
(f) Plaque miu- Parrish (County) - 25 ,225
(g) Han is County - 1, >41,912
(h) Dire, i CM or ma l i >¦ i (DC)
( i ) Aceiv 1. i.0 (,\)
-------
DRAFT
References bO MOT QUOTt CI"! CITE
1. Bureau of Census data, Monitoring and Analysis Division, OAQPS computer
files, 1970.
2. Carpenter, B.ll. Vjnyl Chloride - An Assessment of Fmissions, Control
Techniques and Cost.Research Triangle Institute Report for CSI,, NLRC,
RTI\ July, 1974.
3. Personal Communications between Industry representatives responding
to OAQPS Section 114 letters to LPA personnel, May 1974.
-------
n-r^T _
5.3 CONCENTRATIONS ^ ^ 1 '-<'uul L w'"^
A paucity of c|ata exists concerning the concentration of vinyl
chloride in ambient air. In view of the potential health hazard
associated with VCM, a preliminary field study was initiated to obtain
more extensive and reliable data in the area of industrial emission
sources. The task of obtaining these data for air and water was assigned
to the EPA Regional Offices. Interim procedures were established by EPA
to insure comparability of the data. The initial data from these
surveys will be reviewed in this section. Generally, it would appear that
the Regions had varying degrees of resources and expertise in the area
of air monitoring. In addition, the interim procedure was not followed
religiously in some cases, making comparisons of data between regions
difficult. Levels for residential areas are usually expressed in
parts per million (ppm) VCM, the concentration of VCM occurring in
residential areas not not known with certainty at the present time
but appear to be below 1 ppm - 90 percent of the time based upon the limited
data presently available.
5.3.1 Air
Most of the available data are from instantaneous samples. Because
of the discontinuous nature of the chemical process and emissions, the
values were expected to, and in fact did, range widely. Values were
as high as 33 and 3.4 ppm at distances of 0.3 to 3 miles respectively
from emission sources.
5.3.1.1 Plant I
5.3.1.1.1 Grab samples--Summar.y data from the samples are tabulated
in Table S.3.1 The distance from the center of the plant to the
sites is shown in the second column. Samples taken at site
b -3 - i
-------
Table 5.3.
.1 CONCENTRATION OF VCM IN GRAB
SAMPLES TAKEN
AT PLANT
Plant I -
Grab Samples
Si tp
Pistanrp
km
Nn. nf ^amnlas
Maximum
ppm
-a
ppm
n >i nom.b
A
0.2
0.3
17
6.0
0.52
2
B
0.1
0.2
16
0. 30
0.06
0
1.
lr
C
0. 2
0.3
9
0.22
0.06
0
D
0.1
0.2
9
0.9
U 15
0
o
fr ,ilj
rr_'
LZ: c
>—
E
F
G
0.4
0.4
0. 5
0.6
0.6
0.8
11
9
8
0.6
0. 24
0.14
o.uy
0.03
0
0
0
H
0.5
0.8
10
-
0.03
0
! *
I
0.7
1.1
12
0.40
0.05
0
J
1.0
1.6
8
-
0.03
0
K
1.2
1.9
7
0.24
0.06
0
L
3.0
9.8
8
-
0.03
0
M
0.6
1.0
6
-
0.03
0
N
0.6
1.0
4
-
0.03
0
0
u. 7
1.1
5
-
0. Ui
U
P
0. 5
0.8
6
0.32
0.11
0
TT
0.1
0.2
1
-
0.03
0
UU
0
0
2
0.24
0.22
0
VV
0
0
1
-
0.03
0
WW
0.1
0.2
3
2.6
1.48
2
XX
0.2
0.3
1
0.16
0.17
0
YY
0
0
1
5.7
6.15
1
11
0.2
0.3
1
0.03
0
Values corrected to standard temperature of 25°C.
^Frequency of VCM measured concentrations above 1 ppm.
-------
A i
' ' i ' * *
r: ;,o« qu'jt;
A through P were collected at two hour intervals with Tedlar (R) bags
or syringes. The remaining sampling sites were those where detectable
odors existed. Columns 3, 4 and 5 list the number of samples
collected and analyzed, the maximum concentration of VCM found and
the average at each site. The last column was included to show the
frequency that the concentration of VC exceeded 1 ppm. Over 90 percent
of the values obtained were below minimum detectable values, 0.06 ppm.
Figure 5.3.1 is a histogram of the observed data above the detectable
level. In calculating the mean values, below detectable concentrations
were arbitrorily given values of 0.03 ppm, one-half the minimum
detectable level. Excluding the random samples, the individual values
range from below detectable to 6 ppm.
5.3.1.1.2 Twenty four hour samples-Table 5.3.2 shows the average values uf
VCM in a 24-hour period that were collected on charcoal scrubbers. All
data shown in the Table were corrected to ambient air standard conditions
of 25°C and 1 atmosphere. On May 10, the average value at site A
exceeded 1 ppm. The report indicates, however, that although site A
was 0.2 mile from the center of the plant, it may actually have been
closer to the major source of PVC emissions.
5.3.1.2 Plant IV.--At the present time only the data from the
initial study and summary data are available. Table 5.3.3 shows the
result of the data collected in March. Only three values
exceeded 1 ppm, the highest was 2.2 ppm. The frequency distribution
of these values is shown in Figure 5.3.2. The summary of data collected
in May around this plant are tabulated in Table 5.3.4. One
-------
DRAFT
ro r-OT r"'OTE OR CITE
Table ^ ^ ? CONCENTRATION OF VCM MEASURED IN INTEGRATED SAMPLES
COLLECTED BY LHAkLOaL AbSORBER AT PLANT I, ppm
Date
Si te
5/9 /'74
j 5/10/74
I 5/15/71
Site
A
0. 021
1.15
0.165
B
0
0. 005
0.020
C
0
0.009
0.029
D
0. 141
0.010
I
0. 090
-------
ory^T
c: :,:i qjofl or cue
T'ible 5.3. j. CONCENTRATIONS OF VCM IN GRAB SAMPLES TAKEN AT PLANT IV
IN MARCH 1974
te
Distance, km
Numhpr nf Samples
Maximum
(PPm)
Mean,
DDm
No.-1 DDm
A
0
6
2.2
0.84
B
0.6
3
0. 58
0.40
0
C
0 6
4
1. 26
0. 33
*
i
D
0.6
6
0.29
0.12
0
E
C.8
3
0.24
0.16
0
F
0.8
15
0. 39
<0.17
0
G
0.8
2
-
"0.17
0
H
0.5
1
-
<0.17
0
1
1 3
1
-
<0.17
0
J
1.0
1
-
<0 .17
0
K
1.0
2
-
<0.17
0
L
1.3
1
-
r-H
o
V
0
..
i 1
4.8
L
N
-------
Table 5.3.9. CONCENTRATION OF VCM IN GRAB SAMPLE COLLECTED AT PLANT II IN
MAY 1974
Site
Distance, km
Number nf Saniples
Maximum, nnn
Mean, ppn
A
0
6
1.7
0. 53
B
0.6
21
5.6
1. 6
C
0.6
21
5.8
0.71
D
0.6
19
2.8
0. 54
E
0.8
2
0.10
0.07
H
0.5
3
1.2
0 . 50
I
1.3
2
1.6
1.00
L
1.3
2
BD
BD
N
1.0
1
BD
BD
P
0.6
8
0.08
0.06
Q
0.8
12
1.7
0.34
R
0.5
83
33.0
3.15
s
0.6
i
1. 2
1.20
T
1.0
3
0. 57
0 .21
U
1.0
3
BD
BD
V
0.2
1
BD
BD
6
-------
c
a;
o
i.
aj
o.
>>
u
c
CD
3
CT
-------
.r~TT-r—i i—i I 1 ~
Histogram showing frequency Distribution of VCM Grab Sample Concentration
for Plant IV (K 0.33,^0.40).
-------
r I"* '""I
V I1 I
c: MOT QUOTL 0." r/.[E
instantaneous value of 33 ppm was observed at a distance of 0.5
km from the plant, and one mean value at site B exceeded 1 ppm.
The data from the 24-hour integrated samples indicated the highest
value to be 0.55 ppm (Table 5.3.b.
5.2.1.3 Plant VI--Here again, only -summary data are available.
Table 5.3.6 ana Mgure s.j.j. I.show the observed values at various
distances from the plant, and the frequency distribution of these data.
Only three values exceeded 1 ppm. The range of concentration at the
property line was from below detectable levels to 7.8 ppm.
5.2.1.4 Plant IX--The most complete report was provided by Region IX
which was prepared in cooperation with the National Field
Investigating Center - Denver. However, the data (Table 5.3.7) provided
were from samples on charcoal and are 10 minute averages instead of
instantaneous samples; and hence this data is not comparable with
the preceding. Under these conditions, values as high as 3.4 ppm
were found at a distance of 4.8 km from the plant. Only 12 of the
180 determinations exceeded the 1 ppm level. The overall mean
value calculated was 0.24 + 0.44 ppm.
5.3.2 Summary
Since a great deal of latitude was excercised in implementing
the prescribed procedures, it is difficult to compare the data
from different plants. Based upon the available data, peak values
as high as 33 ppm might be expected in the vicinity of VCM emission
sources. All values obtained are expected to be biased negatively.
5
-------
rlTP ORAFT
NOT QUOTt CR CITE DO NOT QUOTE OR CITE
Taole b.3.5. CONCENTRATION OF VCM IN 24-HOUR AVERAGE SAMPLES
Site
Distance, km
VCM, p p in
MSD
0.6
0.16
NFL
0.6
0.07
SOP
0.3
0.55
DPT
0.2
0.10
CP
1 .0
0.01
-------
DRAFT
DO NOT QUOTE OR CITE
Table 5.3.6. CONCENTRATION OF VCM IN GRAB SAMPLES TAKEN AT PLANT VI, ppm
Date
O.R
1.?
1
3.?
/i. n 40
5/7/79
5/8
5/9
Ma xiinuni
Unl ,,r*
2.069
0. 04 5
7.814
3. 2 1 8
0.666
0.00 3
0. 095
0.078
7.8
0.001
0. 002
BD
0.002
0.002
0. 003
0.002
0.003
0. 336
BD
0. 34
BD
0.168
0.001
0.17
0.002
0.023
0.168
0.181
0.18
BD
BD
0.002
0.001
0.000
0.002
aBelow detection.
-------
PLANT IX - Integrated - 10 Mirute Average as Charcoal Samples
Station Number
Distance from source, km
Run number
0.05
0.15
0.25' 0.25
0.24 0.23
0.11
0.11
0.21
0.11
0.03
0.C5
0.31
0.C5
0.14 <0.05
0.02
0.05
0.C5
0.05
0.29
0.05
0.04
0.03, 0.08
0.33
0.03
0.04
0.02
0.10
0.10
0.11
0.03
0.04
0.06
0.13
0.29
0.03
0.37
0.34
0.08
0.C1
0.16
0.45
0.05 ' 0.04
0.03
0.11
0.C9
0.05
0.C3
0.05
0.10
0.16
0.03
0.07
0.03
0.25
0.09
0.C3
0.04
0.02
0.02
0.05
0.06
0 03
0.06
0.06
0.22
0.15
0.07
0 49
0.10
0.19
/ /
0.29
0.11
0.55 0.04 1 0.53
0.16 ! 0.36
0.07
0.04
0.C5
0.03
0.03
0.32
0.59
0.31
0.33
0.08
0.50
0.14
0.03
0.07
0.10
0.85
0.18
0.26
0.17
0.08
0.05
0.02
0.24
0.03
0.03
0.02
0.06
0.03
0.11
0.05
0.03
0.07
0.03
0.02
0.03
0.05
0.02
0.03
0.07
0.05
0.03
0.07
0.24
0. Co
0.04 0.84 i 0.15
0.02
0.10
0.04
0.06
0.12
3.18 0.16
0.12 0.28 I 0.25
0.53
0.41 10.26 | 0.36 , 0.14 '0.30 0.15
0.33
0.12
0.53
0.85
0.32
10.50
0.45
-------
i :j.k
i v.a
: rr.rr
T iJ.3
t t .a
n.rr
"7.G3
rr.:?
ra.ts
i .a
22-
2C —
18-
16 —
14-
12-
1C-
el
6
4-
0.4 0.8
o
g
rn -1*7
O
=D
£3
rn
£~ mi
~
2.0 2.9
3.2 3.5
7.3 7.8
Concentration VC
ppm
Figure 5.J.S.
Histogram of Frequency Distribution of VCM Grab Sample Concentrations at Plant VI
(X 0.5, iT 0.40)
-------
DR/vr- r
uu HOT QUO 11- ('"> I'irt
Grab samples are expected to lose quantities of VCM due to
continuing reaction in the sampling container, wall loses,
leaks, etc. Indication of VCM losses in these containers range
from 0 to 10 percent per day. Losses of VCM while using charcoal are
expected to be larger than in the containers. Collection efficiency
and recoveries have not been definitively established. Preliminary
data indicate recoveries of 71 to 76 percent when extraction by CS2
is used to recover the VCM from charcoal. For 7 data points in which samples
were collected in parallel and analyzed by two different
laboratories, the values disagreed markedly. The relative standard
deviation about the mean ranged from 5 to 140 percent.
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do n:s- ;''iL on :j!!:
Table 5.3.8. CONCENTRATION OF VCM MEASURED IN INTEGRATED 24-HOUR SAMPLES
COLLECTED BY CHARCOAL ABSORBER AT PLANT IX, ppm
Distance, km
C
late
5/7/74
5/8/74
5/9/74
1.1
0.08a
0.07a
0.103
1.3
0.08
0.08
0.05
3.1
—
0.06
0.05
4.3
—
0.06
0.05
4.5
0.27
0.65
0.27
5.3
0.07
0.04
0.05
a12-Hour Samples
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5.4 tbllMAftb OF AIR QUALITY CONCENTRATIONS
Estimates of vinyl chloride concentrations downwind of two
plant sites were made using available emission estimates and reasonable
meteorological conditions. The estimates were made using Gaussian
dispersion techniques given in EPA's Workbook of Atmospheric Dispersion
1
Estimates. Concentration estimates are for 1-hour averaging times.
Considering possible errors in emissions and dispersion uncertainties,
the estimates may be expected to be within a factor of 3 or 4 of
concentrations that would be measured under the same meteorological
conditions at the same receptors with accurate sampling equipment.
Table b.14 shows the results of the estimates for four
different emission conditions. Wind speed was held
constant at 2 m/sec for all calculations. Since
concentration is inversely proportional to wind speed, a higher
wind speed would decrease the estimates; a lower wind speed would
increase the concentrations estimates. Wind speeds lower than 2 m/sec occur
fairly often, on the order of 3 to 15 percent of the time, at most locations.
Three different atmospheric stabilities were considered. D, or neutral,
stability occurs during day or night when cloudy skies prevail. This stabilitv
also occurs during the transition from unstable daytime conditions
to stable night line conditions and vice versa, t, slightly stable,
and F, moderately stable, both occur at night with clear skies and
light winds. These three meteorological conditions can be expected
to occur during quite a number of hours in a given year.
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DC 140T*OUOTL 0.? CUE
Receptor locations in these model calculations were placed at
positions downwind of the approximate center of the sources and off
the plant property.
For plant A, a computation was made considering the emissions
from 5 point sources of varying heights and from one area source.
These sources are all located within 200 meters of each other. From
the top portion of Table 5.4.1, it is seen that the predicted maximum
hourly concentrations do not differ greatly for the three stabilities,
and are the highest, 4 ppm, for F stability (moderately stable).
Maximum 24-hour concentrations would be much lower.
Concentrations resulting from this plant were also estimated when
a reactor is aborted and over 2270 kg of VCM is vented to the atmosphere
in about 10 minutes. Venting such as this would occur approximately
20 times each year in a PVC plant. Other emissions were assumed to
remain the same as in the above calculation. Under these conditions a
maximum hourly concentration of 29 ppm was predicted to occur under D
stability at 400 meters. Since the other sources contribute less than
3 ppm at this point, the vented release contributes about 26 ppm at
this point. Since the release occurs over only a 10 minute neriod, a
much higher concentration with instantaneous oeaks 5 to 10 times this
concentration, 130-260 ppm, might be expected, based on these calculations,
to occur at this receptor as the pollutant cloud passes. Concentrations
at least 5 times higher, 133 ppm, might occur over a 6 to 10 minute
averaging time at this receptor according to these estimates. Beyond
5.0 km the impact of a spill would be minimal. For both the spill and
non-spill situations, the populations most affected would be those
residing within about 2 km of the plant.
-------
Table 5.4.1. CALCULATED 1-HOUR AVERAGE CONCENTRATIONS OF VINYL CHLORIDE AT SELECTED DOWNWIND DISTANCES
FROM A PLANT WITH MULTIPLE-EMISSION SOURCES
Concentration, pprftb
T
j Distance from
Stabi 1 itv classc .
Stabilitv classd
0
Stabilitv class
:c: plant, km
No spill
With spill1
No spill
With spill'
No spill
With spill
\—
Li—
\.D
~~ 0.25
3.5
18.2
3.8
3.8
4.0
4.0
Or'
o
g, 0.4
2.9
29.3
3.4
4.4
3.9
3.9
CD 0.5
2.6
28.2
3.2
6.1
3.7
4.0
CD 0.8
O
1.7
19.4
2.5
10.9
3.2
7.1
1.0
1.4
14.9
2.1
11.8
3.0
9.5
2.0
0.6
6.0
1.1
8.2
1.9
11.8
3.0
0.4
3.4
0.7
5.4
1.3
9.3
t
5.0
0.2
1.6
0.3
3.0
0.8
5.9
Emission conditions:
Source
type
Emission
rate,q/sec
Height of
emission, m
Point
Point
Poi nt
Point
Point
Area^f
SpillT
18.9
0.63
6.3
8.8
0.5
44.lf
3783.3r
22.9
15.2
7.6
30.5
38.1
6^
15.2
All calculations assume 2.0 m/sec windspeed.
r
Neutral conditions
^Slightly stable.
Moderately stable.
f
Spill of 2270 kg of vinyl chloride released in
10 minutes at a height of 15.2 meters at 338°K (65°C),
^Emissions from a building 110 by 170 m through vents
and windows about 6 m from the ground.
O
o
-o o
m ^
=0
o
--i
rn
-------
ow.,
DO HGI QvJOVi. u.v lift.
Table 5.4.2. CALCULATED 1-HOUR AVERAGE CONCENTRATIONS
OF VCM AT SELECTED DOWNWIND DISTANCES FROM A
PLANTS WITH MULTIPLE EMISSION SOURCES
Concentration
, ppma
ui s cance
Stability U
Stability T
Stability F
downwi nd
Average ^
Peak
Average ^
Peak
Averaqe .
Peak
c
(I'j-i)
emissions
emissions
emissions
emissions
emissions
emissions
0.2
2.2
2.8
2.8
3.3
3.1
3.6
0.3
1.8
2.4
2.5
3.0
3.1
3.7
0.4
1.6
2.2
2.2
2.7
2.9
3.5
0.5
1.4
2.1
1.9
2.4
2.7
3 2
0.8
1.0
1.7
1.5
2.1
2.2
2.7
1.0
0.8
1.5
1.3
2.0
2.0
2 4
2.0
0.4
0.8
0.7
1 .3
1.2
1 .9
3.0
0.3
0.5
0.5
0.9
0.9
1 .5
4.0
0.2
0.3
0.3
0.7
0.7
1 .3
5.0
0.1
0.3
0.3
0.5
0.5
1 .0
10.0
<0.1
0.1
0.1
0.2
0.2
0.5
15.0
<0.1
<0.1
<0.1
0.2
0.2
0.3
20.0
<0.1
<0.1
<0.1
<0.1
0.1
0.2
aAll calculations assume 2.0 m/sec wind speed
^Average emissions:
Point source -- 24.0 g/sec. at 33.5 m.
Area source 1 -- 21.4 g/sec from 150 by 150 meter
building. Assume emission at 6m.
Area source 2 -- 14.4 g/sec. from 180 by 15 meter building.
Assume emission at 6m.
cPeak emissions:
Point source -- 90.5 g/sec. at 33.5m.
Area source 1 — Same as under average emissions.
Area source 2 -- Same as under average emissions plus
a 2 minute spill of 24,000g. (2000g/sec).
-------
< V. -,r 1
For Plant B, one point source and two area sources were considered
under two differenct conditions, average emissions and peak emissions.
Three emission sources are assumed located within 300 meters of each
other in this calculation. In this case the maximum concentrations
are not increased greatly by an increase of a factor of three in the
emissions from the elevated point and/or by a 2 minute spill from the '
area source. However, note that the concentrations are nearly doubled
at greater distances downwind. For Plant B the maximal
concentration, 3.7 ppw, is almost the same as that from Plant A under
normal conditions, 4 ppm.
S- V - ^
-------
REFERENCES
1. Turner, D.B. Workbook of Atmospheric Dispersion Estimates,
EPA, Research Triangle Park, N.C. Publ. No. AP-26, 84p, 1970.
s. i
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cr * "
no NOT Qi'i-I; --
5.5 TRANSFORMATION, TRANSPORT, AND REMOVAL
N° results on the reactions and rates of disappearance
of vinyl chloride from the ambient atmosphere are available at present. Limited
laboratory studies on the stability and persistence of vinyl chloride
in air have, however, been completed.
In addition measurements
recently reported on vinyl chloride in water and sludge indicate that
vinyl chloride dumped into aqueous media are probably lost to the air
relatively rapidly.
Vinyl chloride vapor concentrations in containers of various
materials appear to be essentially constant over periods of many days.
The peak absorption of vinyl chloride in the ultraviolet region is
very far below the solar cutoff around 290 nm so VCM
would not undergo reaction in sunlight in the absence of other reactive
chemical species. When irradiated with simulated solar radiation in
the presence of nitrogen oxides (nitric oxide and nitrogen dioxide),
vinyl chloride in the parts per million concentration range does react
to form a variety of products. The available results indicate a
rate of reaction of about 8 to 10 percent per hour for vinyl chloride.
The reaction products identified include ozone, nitrogen dioxide, carbon
monoxide, formaldehyde, formic acid, formyl chloride and hydrogen
chloride. Several of these products are very irritating.
r
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nr. <•.
UlwM I
DO NOT QUOIT •>:
Although vinyl chloride would disappear significantly in traveling over
longer distances, the conversions anticipated within a few kilometers
downwind of vinyl chloride emission sources would be small. No
mechanism is presently known for removal of vinyl chloride from the
air during the nighttime hours. Biological sinks such as micro-
biological removal in soil may be of significance in depletion of
vinyl chloride over long time periods, but such sinks would not be
expected to be important in terms of urban scale transport of vinyl
chloride. Thus, for a first approximation, vinyl chloride in the
immediate vicinity of vinyl chloride emission sources can be
considered a stable pollutant. The usual meteorological dispersion
equations could thus be applied to approximate concentrations in the
vicinity of emission sources. Because of strong radiation inversions
at night during the fall and winter build-up of vinyl chloride from
emission sources might be of particular concern during such periods.
The noxious gases which are products of vinyl chloride reactions
(and cossibly also from other chlorinated chemicals in industrial
production) should not be ignored. In areas with large
industrial activities involving large volume production of these
chemicals, such products may contribute appreciably to eye, nose,
throat and lung irritation, particularly on sunny days.
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6. ENVIRONMENTAL EXPOSURE AND RECEPTOR RISK
Human exposure to vinyl chloride may occur from air inhalation,
from consumption of food, from intake of water containing vinyl
chloride, and from skin contact. The data available suggest that the
airborne exposure route in general represents the greatest source of
vinyl chloride intake for the population. The highest exposures "to vinyl
chloride occur in occupational situations where the vinyl chloride is
manufactured and where the vinyl chloride monomer, a gas at room tem-
perature and atmospheric pressure, is converted to a polymer. Workers
involved in the polymerization process and in the fabrication of PVC
into end products may be exposed not only to vinyl chloride in the
gaseous phase but may also inhale PVC dusts containing entrapped vinyl
chloride monomer. In this regard PVC particles containing vinyl chloride
may be deposited in tissues.1 To date there is not adequate informatior
on general or occupational population exposure to PVC particles in the
air.
Peak exposures to vinyl chloride in occupational situations may at
times in the past have exceeded 1 ,000 ppm, as for example during reactor
2
cleaning operations, although the highest time weighted average exposures
were probably in the 250-500 ppm range.3,4 The threshold limit value for
set at
vinyl chloride was at one time/500 ppm based upon its narcotic properties.
After reports of liver damage due to vinyl chloride at exposures below
500 ppm were available the TLV was reduced to a 200 ppm time weighted
average exposure for a forty-hour work week, with a 500 ppm ceiling for
C - 1
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5 6
peak exposures. * When it became evident from animal studies that
vinyl chloride produced angiosarcoma of the liver at exposures as low
as 250 ppm, and when cases of liver angiosarcoma were reported from
workers in PVC production plants, an emergency ceiling TLV of 50 ppm
was established and a recommendation to set a permanent standard at a
no detectable limit based upon an analytical procedure capable of
detecting vinyl chloride at concentrations of 1 ppm was made by the
Department of Labor.6 That recommendation has recently been modified
and a permanent standard promulgated which calls for a maximum 8-hour
worker exposure to vinyl chloride of 1 ppm with peak 15 minute exposures
not to exceed 5 ppm. Since establishment of the 50 ppm emergency
standard additional animal studies have shown vinyl chloride to be
a carcinogen in experimental animals at 50 ppm exposure levels.6'^
These data are reviewed more fully in the following sections.
Among the general population not involved directly in VC/PVC manu-
facture and product fabrication, the greatest sources of vinyl chloride
exposure are estimated to be or to have been from aerosol products containing
vinyl chloride propel 1 ants and from atmospheric emissions in the vicinity
of industrial sources. Studies on vinyl chloride aerosols used in home
situations indicate that peak exposures in excess of 100 ppm can occur.®
Time weighted average air exposures to vinyl chloride in aerosol products
would, of course, depend upon the frequency and conditions under which
these products were used. To date over 100 aerosol products have been
identified which either contained or currently contain vinyl chloride.
For populations residing in the vicinity of industrial sources pre-
liminary date, described earlier, show peak exposure of 33 ppm and
24-hour samples as high as 1-2 ppm. Over 90% of samples, both peak and
24-hour measurements, were below 1 ppm.9 it should be noted that the
(r
-------
risk to health may be related to the exposure pattern to vinyl chloride,
i.e. intermittent peaks, a 40-hour exposure each work week or a continuous
low level exposure.
Vinyl chloride concentrations of 2-3 ppm
and at times higher have been recorded from manufacturing plant effluents.
although it is unlikely that such contamination would persist in water downstream
which might be used for drinking purposes, due to the tendency for vinyl
chloride to escape from water into the air.9 Water contamination with
vinyl chloride from PVC piping may be a problem althouqh available data
do not indicate this to be the case. To date, there is no
indication that drinking water contains detectable levels of vinyl
9
chloride. Food, either beverages or solids oackaged in PVC containers,
may contain vinyl chloride as a result of leaching, but the full
extent of such a potential problem is at present unknown. A World Health
Organization Report tentatively estimates that human intake of vinyl
chloride, based upon a limited range of food is on the order of 1 ng per
person per day J ^
For the general population, it is impossible to quantitate
the relative importance of various vinyl chloride exposure sources on an
individual basis based upon current data. However, if tne assumptions regarding
levels of contamination are correct, tne relative importance of these sources
can be estimated. This estimate and the assumptions in these calculations are
shown in Table 6.1.1.Conclusions drawn from this analysis are, of course,
dependent upon the assumptions which are made. These estimates assume
equal absorption of vinyl chloride from food and water in the gastrointesti-
nal tract compared to vinyl chloride absorbed by the lungs from the air.
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Table 6.1.1 RELATIVE IMPORTANCE OF VINYL CHLORIDE SOURCES
FOR THE GENERAL ADULT POPULATION (mg VCM)
1 o 3
Food Water Air Total
0.002 -- 3.0 3.002
^Assume 2 Kg ingested daily containing an average of 0.001 ppm VCH by weight
resulting in an intake of 2 yg/day. A World Health Organization Report
estimates the levels of vinyl chloride in food may be on the order of 1
microgram per person, per day, based upon tentative calculations from a
limited range of foods.
^Assume 2 liters ingested daily containing no detectable levels of VCM. To
date there is no indication that drinking water contains detectable levels
of vinyl chloride.
o 2
Assume inhalation of 20 m per day containing 0.05 ppm vinyl chloride by
volume.
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DRAFT
00 MOT Q'JOTL OK CITE
This may or may riot be true. Based upon these calculations, it is
evident that the airborne source, in general, can be considered the most
important route of exposure to this substance among the population.
Specification of the risk to health among the general population
associated with the given airborne exposure to vinyl chloride is ex-
tremely difficult in large part due to the lack of information regarding
responses to vinyl chloride at ambient dose levels in both animals and
man. Further, the data available, regarding adverse effects attributable
to vinyl chloride in man do not include adequate measures of exposure
which may have been responsible for such damage.
In considering the risk to human health from vinyl chloride exposure
in the population, it is important to keep in mind that angiosarcoma
of the liver, though dii invariably fatal disease, is not necessarily
the most significant health effect associated with vinyl chloride.
Other cancers may also be involved and non-malignant damage to the liver
may affect a far greater proportion of the exposed population than those who
develop angiosarcoma. To date angiosarcoma of the liver has been con-
sidered an extremely rare disease among the general population. In a
survey by the American Cancer Society only one case of angiosarcoma
u -
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r»n a. r;T
ij i > ' * • I
DC P* (~!T£
12
of the liver was recorded among 78,000 deaths. However, the possi-
bility that the frequency of this disorder has been greatly under-
estimated must be considered. Shown in Table 6.1.2 are the results of
several studies examining the frequency of liver angiosarcoma among
workers exposed to vinyl chloride.
Table 6.1.2
FREQUENCY OF LIVER ANGIOSARCOMA
AMONG DECEASED VINYL CHLORIDE WORKER^3-16)
Number
of Deaths
Reported Frequency of Liver Angiosarcoma
Number
Percent
a'3
161
5
3.1
b'4
24
3
12.5
c15
20
-
-
d'«
109
6
5.5
Total
314
14
4.5
While it is likely that these reported cases of liver angiosarcoma occurred
among workers exposed to levels of vinyl chloride many times greater than
that normally found in the ambient air, it is also noteworthy that compared
to the general population (1 case in 78,000) the relative risk of developing
liver angiosarcoma among those exposed individuals by combining all these
data is estimated to oe approximately 3,000 times greater. Such a
relative risk represents a striking
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DR.'.rr
CZ NOi QJuif OR an
statistically significant difference (p << 0.01) in the frequency of
liver angiosarcoma among those exposed to high levels of vinyl chloride
compared to those in the general population exposed to much lower
levels.
In attempting to assess trends in incidence of liver angiosarcoma among
the population, it is important to recognize that other chemicals
besides vinyl chloride may be contributing to such a phenomenon. Included
in such a list would be materials with similar chemical structures to vinyl
chloride as well as arsenicals and thorotrast, both of which have already
been associated with angiosarcoma of the liver. ^ ^
-------
6.1 REFERENCES
¦\:t Qi'.ift 0:1 cite
1. Volkheimer, G. Hematogenous Dissemination of Ingested PVC
Microparticles. Paper presended at the Working Group on Toxicity
of Vinyl Chloride-Polyvinyl Chloride, the New York Academy of
Sciences, New York City. May 10-11, 1974.
2. Rowe, V.K. Experience in Industrial Exposure Control. Paper
presented at the Working Group Toxicity of Vinyl Chloride-Polyvinyl
Chloride, The New York Academy of Sciences, New York, May 10-11,1974.
3. Daniel, Roger L., Dow Chemical Company. Testimony presented at
Public Hearing - Proposed Standard for Occupational Exposure to Vinyl
Chloride, U.S. Department of Laoor, Washington, D.C., June 25, 1974.
4. Dernehl, Carl V., Associate Medical Director, Union Carbide Corpora-
tion. Testimony presented at Public Hearing - Proposed Standard for
Occupational txposure to Vinyl Chloride, U.S. Department of Labor,
Washington, D.C., June 25, 1974.
5. Key, M. Introductory Remarks. Presented at the Working Group Toxicity
of Vinyl Chloride - Polyvinyl Chloride, The New York Academy of Sciences,
New York City, May 10-11, 1974.
6. Federal Register. Vol 39, #92, May 10, 1974. pp. 16896-16900.
7. Maltoni, C. and G. Lefennne. Carcinogenicity Bio-Assays of Vinyl
Chloride: Current Results. Paper presented at the Working Group
Toxicity of Vinyl Chloride - Polyvinyl Chloride, the New York Academy
of Sciences, New York City, May 10-11, 1974.
-------
("AFT
D1} n.:r quo it on cue
8. Gay, B., W. Lonneman, K. Bridbord and J. Moran. Exposure to Vinyl
Chloride in Aerosol Products. £per presented at the Working
Group, Toxicity of Vinyl Chlordie - Polyvinyl Chloride, The rlew York
Academy of Sciences, Hew York City, May 10-11, 1974.
9. EPA Urges Prompt Steps by Chemical Industry to Reduce Vinyl Chloride
Air Emissions. Environmental News, EPA, Washington, D.C., June 11,
1974.
10. Wagoner, Joseph, NI0SIH. Testimony before United States Senate,
August 21, 1974.
11. Report of a Working Group on Vinyl Chloride, World Health Organization.
I ARC Ijitej^ijJ. J&qlin "jjca 1_ Re_po r t No. 74/005, Lyon, June 24-25, 1974.
12. Selikoft, Dr. I.J. Testimony Presented at PuDlic Hearing - Proposed
Standard for Occupational Exposure to Vinyl Chlordie, U.S. Department
of Labor, Washington, D.C., June 25, 1974.
13. Menson, Richard R., John M. Peters and Maurice N. Johnson.
Proportional Mortality Among Vinyl Chloride Workers. Lancet,
pp. 397-398, August 17, 1974.
14. Nicholson, William J., E. Cuylor Hammond, Herbert Seidman
and Irving J. Selikoff. Mortality Experience of a Cohort of
Vinyl Chloride Workers. Paper presented at Working Group on
Toxicity of Vinyl Chloride - Polyvinyl Chloride. New York Academy
of Sciences, New York City, May 10-11, 1974.
15. Holder, Ben. The Dow Chemical Company Testimony Presented at
Public Hearing--Proposed Standard for Occupational Exposure to
Vinyl Chloride. U. S. Department of Labor, Washington, D.C. June 25,1974.
-------
n n * ct
L \:M !
i>,i :>-r .v i.yj-j: no f|T£
L> ) l*J 1 7»'Oh. V»M vl I l-
16. Wagoner, Joseph K. National Institute of Occupational Safety and
Health Statement Presented before the Subcommittee on the Environment
fnmmprrp rwmittoo n 9 c;Pnfltp. Washington, D.C., August 21, 19?d
17. deSilvo Horta, J., J.D. Abbott, L. Cayolla da Mutta, and M.L. Roriz.
Malignancy and Other Late Effects Following Administration of Thoro-
trast. Lancet 2^:201-250, 1965.
18 Regelso, W., V. Kim, J. Jspina, and J.F. Holland. Hemangioendothelial
sarcoma of Liver from Chronic Arsenic Intoxication by Fowler's
Solution. Cancer, 21_: 514-522, 1958.
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DO
7.1 TOXICOLOGY
7.1.1 Introduction
The effects associated with vinyl chloride exposure include narcosis
associated with acute exposure, and liver and low grade kidney damage
similar to that associated with other halogenated aliphatic hydrocarbons.
Acroosteolysis has also been observed among workers exposed to vinyl
chloride. This disorder is characterized by degeneration of bones in
the fingers and has been associated primarily with direct contact with
polymerized material (PVC) and high levels of gaseous monomeric vinyl
chloride. 1 This response is unique among the occupational hazards
resulting from exposure to the aliphatic chlorohydrocarbons. The recent
discovery that vinyl chloride induces carcinogenic changes in experi-
mental animals and the appearance of liver angiosarcoma among PVC workers
also appears to be a response to vinyl chloride exposure. ^
Although there has been no systematic quanitative assessment of the
toxicity of the many halogenated hydrocarbons, vinyl chloride has until
recently been considered one cf the least toxic of the aliphatic chlorohydrocarbon
8a
chemicals. 1
Carcinogenic activic.v of vinyl chloride has been confirmed in
several species of experimental animals and associated with both acute
and chronic low level exposure when the experimental period was sufficient
in time to permit tumors to appear.2-5 The appearance of hepatic angio-
sarcoma, malignant lesion in the liver of experimental
animals ,and the discovery that this equally rare lesion in man is associated
-------
nn WAFT
00 tier QUOTE OR CITE
with occupational exposure to vinyl chloride circumstances
has served to underscore the
predictive value of experimental toxicology. Questions have also been
raised regarding the safety of other chemicals structurally related to
vinyl chloride that traditionally have been considered of low order
toxicity.8 A literature review of the toxicology of vinyl chloride
has recently been presented by Marsteller et al, 1974. A
summary of this information is presented in Appendix B. Since vinyl
chloride is now a recognized chemical carcinogen that has been detected
in the ambient air near monomer and polymer production facilities in the
United States, its presence in the environment represents a potential
public health hazard.
7.1.2 Acute Effects
The early experimental toxicology of vinyl chloride was limited to
acute exposures. These early studies employed a variety of experimental
animals and were limited to very short exposure periods. The results of
these studies have been reviewed by von Oettingen,^ Mastromatteo
* , 10 9
et al- and more recently by Marsteller et al.
In general, these investigations suggested vinyl chloride was of low order
acute toxicity, anesthetic in action, ancl had little capacity to cause
injury to the liver or kidneys- The duration of tnese exposures rangea rrom
minutes to hours. These observations lea to consideration of vinyl chloride
9
for use as a general anesthetic. The anesthetic effects were uflen
accompanied by
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¦'¦^vA£te c:? cite
do o;.:o:e or cite
cardiac irregularities with some suggestion of cardiac sensitization.
The effective narcotic level in mice exposed to vinyl chloride for one
minute ranged from 86,000 . to 123,000 ppm. Approximately 170,000
ppm was required to induce narcosis in dogs and rabbits over the same
exposure period. Cardiac irregularities were observed in electrocardio-
grams of dogs exposed to 100,000 ppm for less than 4 nours.
In addition, the observation of other side-effects suggested further
systemic disturbances associated with acute exposure. Guinea pigs
exposed to 5,000 ppm of vinyl chloride f°r a ^0 rninute period
displayed pulmonary edema and hyperemia (excess blood) in the kidneys
and liver on autopsy-^ Although all pathological parameters
appeared normal in rats exposed to vinyl chloride levels up to
100,000 ppm over a thirteen day period, advanced lymphocytic hyperplasia
of the spleen was observed!'1 At lower exposure concentrations and extended
exposure periods (50,000 ppm; 19 days), increased liver size was observed
in these experimental animals (Sherman rats)!2 Pathological8/3™™3*™"^^ con_
jestion at the cellular level in the liver of these experimental animals;
however, parasitic cysts were also observed in the liver of these
animals which confounds conclusions regarding acute effects anc*
systemic damage associated specifically with vinyl cnloriae exposure. Although
the results available suggest only marignal systemic effects, there are
some indications that vinyl chloride is not simply absorbed and exchanged
in the lungs but distributed throughout the body with pathological
alterations observed in the 1 iver Sidneys and spleen. Therefore,
effects such as pulmonary edema, tracheal irritation, hyperemia of the
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liver arid kidneys, cardiac arrhythunia and hyperplastic chanaes in thp
spleen and liver may be subtle side effects of acute vinyl chloride
exposure that suggests functional interaction in various organs and
systems of the body. A summary of these and other experiments are
presented in Appendix B.
7.1.3 Chronic Inhalation Toxicology
While investigations of short duration with high exposures are
useful in determining lethality and gross toxicity, chronic effects
associated with continuous or repetitive exposure to lower levels of
vinyl chloride are more important in evaluating possible environmental
hazards. Several investigations designed to assess chronic effects
associated with repetitive exposures to vinyl chloride began in the
13
early sixty's. Torkelson, Oyen and Rowe reported results of studies
using several species of animals (dogs, Guinea pigs, rats and
rabbits) exposed to levels of vinyl chloride ranging from 50 to
500 ppm. The results of these studies noted that all species of
experimental animals exposed to vinyl chloride at 500 ppm
administered daily 7 hours/day over a four and a half month period,
were normal with respect to appearance,
growth and mortality. While several blood parameters (serum enzymes)
used to monitor functional disturbances of the liver were found to be
within normal limits, there was an increase in liver size observed in
male rats that was not apparent in female animals. In addition, central
lobular degeneration of the liver and renal tubular damage in the kidneys was
apparent upon microscopic examination of the various tissues excisea
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from animals sacrificed at the end of the experimental period. Since
considerable liver damage is required to alter serum enzyme levels used
14-16
to monitor liver function, histopathologic changes such as those observed
in these studies may be an important parameter in evaluating beginning
liver damage which might not be detected by serum enzymes. Similar
effects were observed in the liver of male rabbits exposed to 200 ppm of vinyl
daily
chloride administered for 7 hours / over a six month period with
necrosis ana periportal cellular infiltration in the liver
was not observed in the females. Thls observation suggests a
sexual difference in the response of male and female rabbits to vinyl
chloride and alludes to a possible hormonal influence. Other experiments sugqests
that carcinogenic agents may modulate the activity of steroidal hormones ,17"19
While the liver of male and female rats remained
increased in size at this dose level (200 ppm)5 no apparent microscopic-
pathology was observed.There were no apparent kidney disturbances noted
among the various animals exposed to this dose level (200 ppm).
Increased liver size was sustained even when exposure was reduced
to 100 ppm for 2 hours daily over the 6 month period of the experiment.
However, it is important to note that
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liver to boay weignt ratios were not statistically different from controls
at these lower dose levels. A further reduction in exposure to
50 ppm for 7 hours ppr day for S davs npr wppk
administered over a 6 -month period produced no evidence of liver
Size
abnormalities in ' or microscopic appearance in these experimental
animals. Despite the lack of statistical" significance,
these toxicologists placed sufficient weight on their
observations of subtle liver damage observed in several animal species to
recommend adjustments in the establlsnea industrial standards for
permissible exposure to vinyl chloride as early as 1961.
The experimental protocols used in this investigation
were limited to a six month period and did not reserve treated animals
for longevity studies. It is conceivable that carcinogenicity of
vinyl chloride would have been known nearly fifteen years ago had the
effects of longevity been studied in these early studies.
(2^°>21 i -i j i tn
Attempts by Viola et al. to tlevelop an animal model «-o
investigate the pathogenesis of acroosteolysis
revealed convincing evidence of systemic toxic effects in a wide
variety of organ systems. These subacute studies provide a more
complete description of systemic effects associated with exposure to high
concentrations of vinyl chloride monomer extended over a twelve month
period. While attention is focused upon the liver of these
experimental animals (Rats, Wistar strain) pathology was noted in the
kidneys, arteries, skin, bones, brain,and nerves. A fibrosclerotic
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reaction appears to be a common denominator in the biologically diverse
tissues of these various organs. A fibrotic lesion in the liver appears
to be important in evaluating the pre-cancer state of liver
(22)
angiosarcoma/ '
These observations provided evidence of the permeation of vinyl chloride
throughout the body and suggested interference with membrane structure
(e.g. lipid peroxidation) with a compensatory repair response
(endothelial proliferation). Carbon tetrachloride also produces a
peroxidative degradation of structural lipids particularly in the
23,24
1iver.
There have been other published reports in the Russian and European
literature that provide evidence of alterations in cardiac function,
and
ypertension,/increased adrenalin and neural activity in the brain of
several animal species subjected to low chronic exposure levels of vinyl
chloride (Appendix B). These experiments suggest the possibility of
cardiac disturbances and behaviorial changes in man exposed to
vinyl chloride "nder occnational circumstances25
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A summary of chronic systemic effects from inhalation of vinyl
chloride observed in experimental animals include:
• Alteration in liver function. There may be sexual differences
in nature of the response of the liver of male and female
animals. A fibrosclerotic reaction in necrotic areas of
the liver with evidence of a hepatic regenerative process
has been noted. Therefore, vinyl chloride may be considered
a chemical hepatotoxin.
• Disturbances observed in the circulatory system include
irregularities in cardiac function, endothelial fibrosis in
arteries and alteration circulating white blood
cell levels. Hypertension has also been observed and
may be related to induced adrenalin activity similar
to other aliphatic chlorohydrocarbons.
o Exposure concentrations, duration of exposure
and frequency of exposure appears to be important aspects
that determine the nature and severity of toxic response.
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The significance of the evidence from chronic studies appear
to have been underrated since many of these experiments have not
been repeated on a large scale until recent discovery of
carcinogenic activity. Although attempts were made to establish a
dose-response relationship, there has been little or no data available to per-
mit quantitative analysis of the systemic response to vinyl chloride
exposure. Qualitatively, it is important to recognize the
significance of repetitive exposures and exposure durations that permit
? C 1 *3
observations of time-dependent response Dhenomena.
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Co A FT
p r ~ r-
'1 ' (r r> .^,rr
7.1.4 Carcinogenicity of Vinyl Chloride ' ~ "'v ' u
There have been three investigations that deal with the
2
carcinogenicity of vinyl chloride, Viola et al
Mai toni and Lefemine,4 and Keplinger et al 5
The first evidence of carcinogenic effects associated with exposure to
9 21
vinyl chloride was reported by Viola et al- '
These investigations involved twenty-five Wistar (AR/IRE)
albino male rats (150 gm body weight) exposed to 30,000 ppm of V(M
for 4 hours a day, 5 days a week for 12 months. The tumors observed
under these subacute exposure conditions are presented in Table 7.1
Although these experiments apparently were not specifically
designed for investigating carcinogenicity, there was sufficient
evidence of a tuniorogenic response to warrant further
investigation. Particular attention focused upon the following aspects
of tumorogenicity of vinyl chloride in Wistar rats subjected to
subacute exposure conditions:
• Tumor multiplicity with neoplastic lesions observed in
several tissues.
» The presence of Zymbal gland tumors. These sebaceous glands
located in the ear of rodents are particularly responsive to
other chemical carcinogens (e.g. acetyl-aminofluorine: AAF,
polynuclear aromatic hydrocarbons: PNA such as 9,10-dimethyl-
1,2 benzanthracene; urethan; 4 amino-stibenes, benzidine).
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Since the majority of tumors observed were epidermoid carcinomas
of the skin, these investigators concluded that the cutaneous system
(skin) was the system most susceptable to the oncogenic effects of
vinyl chloride (Tables 7.1.1 and 7.1.2)
It is important to note, however, the absence of liver angiosarcoma
in these animals subjected to high levels of vinyl chloride
monomer for nearly half of their life-span.
Therefore, a more comprehensive, quantitativeand systematic
series of investigations were initiated in Europe and the United States
to confirm the carcinogenicity of vinyl chloride with particular
emphasis placed upon the dose-response relationships in several studies
of experimental animals.
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Tables 7.1.1 TYPES OF TUMORS OBSERVED IN MALE WISTAR
a
RATS EXPOSED TO 30,000 ppm OF VINYL CHLORIDE
Wistar Tumors
Rat<;
Skin
I un£s
Bones
number
i
Mutocpidermoid
carcinoma
Adenojcanihomj
Osteochondroma
2.3
Epidcrrioid
caicinom i, kera-
tinizing t> pi:
No tumor
No tumor
4
Epidermoid
carcinoma, kera-
tinizing t> pe
Adenocarcinoma
No tumor
5
Papilloma, keratotic
No rumor
Osteochondroma
t>pc
6
Epidermoid
carcinoma
No rumor
Osteochondroma
7
Epidermoid
carcinoma
No tumor
No tumor
8
• MiKiiLpidiTmoid
carunom l
No tuinor
Osteochondroma
14
i tpidernoid
cari.inor.iJ
No tumor
No lunior
16. 17
. Epidermoid
cjicinonu
Adenocarcinoma
No tumor
21
, Epidermoid
carcinoma
No tumor
No tumor
22
hpiJl . ,IOld
can.mo.na
Adenocarcinoma
Osteochondroma
23
• Epide'rnoid
carcinoma
No tumor
No tumor
24
Epidermoid
carcinoma
Mucus-producing
jdenoc j'cinonia
(alxeolar cell
carcinonu0) •
No tumor
25
Epidermoid
carcinoma
N'o .umor
tumor
26
Fpidt. niioid
carcinoma
Squjnioii\ nil
ca'L'inoma
No tumor
aInhalation exposures were
conducted 4 hours/day, 5 days/week over a 12 month period
From Viola. P.L. et al.2
7 -
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Table 7.1.2 TUMOR INCIDENCE IN MALE WISTAR RATS
EXPOSED TO VINYL CHLORIDE 3
Tumors
Vinyl chloride
Total
ppm
Animals
Skin
Lung Bones
Total
30,000
26
17
6 5
25
Controls
25
—
— —
0
a Inhalation cf 30,000 ppm vinyl
chloride, 4 hours/dav, 5 davs/week over 12 months.
From Viola, P.l. et al.(2)
n
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In Europe, additional investigations began in late 1971 under the
auspecies of Maltoni and Lefemine.^ A series of 14 correlated
and integrated experiments were designed to elucidate the relationship
of vinyl chloride carcinogenicity to route of administration,
exposure concentration, length of exposure, species response variation and
age dependent effects. The basic design of these studies placed
particular emphasis upon controlled exposure conditions and a compilation of a
tumor incidence profile from observations over the entire life
span of the experimental animals in response to inhalation of vinyl
chloride of high purity (99.99percent). The preliminary results of this
initial study have been reported (Table 7.T.?. The percentage of
Sprague-Dawley rats with various types of tumors observed following
cessation of vinyl chloride exposure at various dose levels is
presented in Figure 1.1.The information available from these early
studies indicate that vinyl chloride carcinogenicity is dose-dependent.
Total tumor incidence appears to decrease with decreasing concentrations
of vinyl chloride and was also observed to be dependent upon duration
of exposure as well as concentration. Liver angiosarcoma and nephro-
blastoma of the kidneys of these Sprague-Dawley rats do not appear to
be as concentration-dependent as the generalized tumorogenic
response (Figure 7.1.1). These investigators suggest that liver angio-
sarcoma and nephroblastoma may be more dependent upon duration of
exposure than upon the concentration of vinyl chloride administered.
The basis for this suggestion stems fron the observation that
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Figure 7.1.1
The Concentration Deoendency of Selected Neoplasia in
Sprague-Dawley Rats.a
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4
a Derived from Maltoni C. and Lefemine, G., 1974. The incidence of
neoplasia determined at 131 weeks following the onset of exposure.
Animals were exposed to various concentrations of vinyl chloride for
4 hours per day, 5 days per week over a 52 week period. Control
animals were void of tumors.
6
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PR" FT
c: '::t -'-'m c~ :.'T
all of the tumors observed under reduced exposure conditions
were carcinomas of the Zymbal gland. There were no angiosarcomas or
nephroblastoma in the liver and kidneys observed under reduced durations
of exposure to high levels of vinyl chloride. However, information is
available only at the higher exposure levels of vinyl chloride (10,000
and 6,000 ppm).
There have been five distinct types of tumors observed in the
4
investigations of Maltoni and Lefemine. Angiosarcoma, narti-
cularly in the liver of mice and rats were found. This tumor type was
also observed in the subcutaneous tissue of offspring from vinyl chloride
exposed pregnant rats. Zymbal glana carcinomas and renal nephroblastomas in
rats as well as mammary carcinomas in mice as a consequence of
metastases from pulmonary adenomas were also observed. It is
important to note that Zymbal gland carcinomas, nephroblastomas and
liver angiosarcoma were never observed to occur spontaneously in the
strain of Sprague-Dawley rats used in these studies.4
Selected early conclusions reported by Maltoni and Lefemine
from their preliminary studies are as follows; (note that
parenthetical material has been added fqr clarity.):
*"Vinyl chloride is oncogenic (carcinogenic) under the
experimental conditions employed. It induces, in rats,
carcinomas of the Zymbal glands (sebaceous glands nfthe
skin located in the ear), nephroblastomas ( kidneys)
and angiosarcomas in the liver and other sites; in
mice, liver angiosarcomas, pulmonary adenomas (in the
lungs) and mammary carcinomas ( breast )."
7
-------
*"A direct relationship exists between dose (concentration)
and length of treatment (exposure duration) and the neoplastic
response (carcinogenicity)."
*"Blood vessel ectasis and endothelial hyperplasia,
associated or not with cellular atypia, are often observed
in the liver and in other organs and tissues in treated
animals, with or without angiosarcomas. Therefore, the
effect of vinyl chloride on blood vessels and endothel 1 a 1
should be considered systemic."
The American investigation began after the onset of the
European studies and were designed to compliment the work of Maltoni
and Lefemine. ' While the experimental design differs to some extent
from those of Maltoni and Lefemine, the early results from investigations
5
conducted by Keplinger et al. confirm the capacity of vinyl
chloride to induce hepatic angiosarcoma in mice at an exposure level
of 50 ppm. Angiosarcoma was also identified in the liver of male rats
and hamsters exposed to 2500 ppm and one female rat exposed to 200 ppm. Further-
more tumors at other sites of the body were also observed in mice
and include those identified in lungs, mammary glands and skin. There-
fore, additional evidence of multifocal carcinogenicity of vinyl chloride
2 4
is consistent with that of Viola et al. and Maltoni and Lefemine.
It is important to note the appearance of liver angiosarcoma in a third
species of experimental animals exposed to gaseous vinyl chloride; the
Golden Syrian hamster. There have been no tumors observed in
control animals at this time. Although there has been a high mortality
rate among experimental animals in these studies, it is important to note
-------
00 NCt or c,te
that angiosarcoma of the liver has been observed in mice exposed to
50 ppm of vinyl chloride following periods of exposure of only 6 months
duratioa
This tends to confirm the observations of Maltoni
and Lefemine in rats at this exposure level, an<± helps to clarify
some questions raised regarding whether liver angiosarcoma occurs
within the life span of experimental animals.
In the
Maltoni experiments, liver angiosarcoma was observed at 50 ppm only
after 130 weeks of observation, suggesting that at dosages below 50 ppm,
effects might not occur within the lifetime of rats. The American
studies would suggest that,at least in mice, this is not so.
The preliminary results from the American and European investigations
provide convincing evidence that vinyl chloride is an active chemical
carcinogen. It has been shown to induce tumors in various organs in
three species of animals at exposure concentrations down to 50 ppm.
Angiosarcoma has also been observed in three species of animals;
Sprague-Dawley rats, Syrian golden hamsters and mice. Angiosarcoma
of the liver has also been observed in rats and mice in two research
laboratories at 50 ppm exposure concentrations. It is noteworthy
that Wistar strain rats display a multiple carcinogenic response following
inhalation of vinyl chloride with tumors appearing in several different organs
(bone, kidneys and skin), but this strain Df r^ts is apparently refractory in the
development
of liver angiosarcoma.
2,5
Furthermore, recent evidence
suggests that the oncogenic response in the liver of experimental
animals is not restricted to angiosarcoma since hepatomas have also
been observed as well.
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4,5
While two laboratories'are investigating the dose-response
relationships of vinyl chloride carcinogenicity, only
the studies of Maltoni and Lefemine are sufficiently advanced to
provide information in this regard. However, the published data
available are preliminary, largely qualitative in nature and of limited
value for statistical analysis and risk assessments (Appendix A).
Specific attention is drawn to the presentation of tumor incidence and
the absence of data regarding the precise number of animals bearing more than
one tumor type ( Table7-3 ). Although total tumor incidence appears to
be more dependent upon exposure concentration, this dependency is not
readily apparent regarding liver angiosarcoma and is absent regarding
nephroblastoma of the kidneys(Figure 7.1).Liver angiosarcoma and
nephroblastoma appear to be more dependent upon exposure duration
4
than exposure concentration. It is important to recall the
preliminary nature of the data available and the nature of carcinogenicity.
Cancer is self replicating and largely irreversible depending
upon the type and size of tumor development. Liver angiosarcoma
in man is largely an incurable,fatal disease. Therefore, exposure
to vinyl chloride at any concentration for any period of time may not be
without risk.
Another important consideration from the early results of Maltoni
and Lefemine is the possibility of transplacental carcinogenicity.
Further attention is also drawn to the recent evidence of vinyl
chloride mutagenicity thatrequires biotransformation (metabolic
activation) by liver detoxification enzymes before effects are observed
Z.
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DRAFT
00 tIC7 QUOTE DR CITE
in bacterial test systems.^27^
While somatic mutations may provide
a basis for carcinogenicity in the immediate generation, dominant germinal
mutations could be expressed as an increase in spontaneous abortions.
In this regard, preliminary evidence suggests an elevated incidence
of spontaneous abortions among the families of polyvinyl chloride
workers. These considerations underline the need to further
evaluate the effects of vinyl chloride upon reproductive compentency
including fertility, fecundity, and pre-peri-natal toxicology and
transplacental carcinogenicity' including possible transmission of
this hazardous material from the workplace to the home.
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7.1.5 Absorption, Distribution, Metabolism, and Excretion
In the review of aliphatic chlorinated hydrocarbons by von Oettingen, 11
levels of vinyl chloride were determined in the blood of cats subjected
to acute exposure conditions. Appendix ti also). Exposure to 100,000
ppm for less than 4 hours produced vinyl chloride concentrations of 15 to 17
mg percent >g/100 mg blood) in these animals. Respiratory and cardiac
arrest were observed as blood levels of vinyl chloride reached 27 to 30 mg per-
cent and exceeded 40 mg percent respectively. Approximately, 82 percent of the
inhaled VC was eliminated immediately from the lungs in these experiments.
20
The observation of Viola et. al in Wistar rats exposed to
10,000 ppm for 60 minutes tends to support conclusions regarding the
lungs as the principle excretory route of vinyl chloride. The con-
centration of vinyl chloride decreases rapidly in expired air, blood,
urine, brain, liver and kidneys during the first hour followiing exposure
in those experiments. There was essentially no
detectable levels of vinyl chloride in these animals at 3 hours
following exposure. Analysis of the distribution of vinyl chloride
among the formed elements and the fluid media of the blood indicates
that red blood cells appeared to have a greater affinity for vinyl
chloride than serum. Although these observations are limited in scope
and detail, they provide qualitative evidence that vinyl chloride is
absorbed, distributed throughout the body,and eliminated by the pulmonary
and urinary excretory routes. It would appear from these early studies
that vinyl chloride was not metabollzed,was excreted essentially
unchanged and tended to support conclusions regarding its low order of
toxicity.
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However, with the evidence of the more recent studies on
carcinogenicity, investigations regarding the metabolism and
pharmacodynamics of vinyl chloride under controlled conditions have
been undertaken by Hefner et al. ' Preliminary results of this
investigation indicate that vinyl chloride monomer apparently
metabolized to polar metabolites that are excreted primarily in the
urine of animals subjected to an initial 50 ppm exposure level.
There appears to be very little excreted in the expired air as unaltered
vinyl chloride at this exposure concentration.
The early conclusions drawn from these investigations by Hefner
et al. are as fol1ows
There appears to be a metabolic threshold for metabolism
of vinyl chloride. Sprague-Dawlev rats exDosed to vinyl
chloride below 100 ppm appear to metabolize vinyl chloride
fairly readily. Exposure to vinyl chloride levels in
excess of 200 ppm reduces metabolism considerably. This
also suggests that the metabolic pathway available at
levels of vinyl chloride below 100 ppm can be saturated.
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®Vinyl chloride appears to be metabolized via alcohol
dehydrogenase since it can be inhibited by pyrazole (1,2
ovrazole ancl ethanol. It is important to note that the
metabolism of vinyl chloride did not appear to be inhibited
by SkF-525-A that is used to block the activity of some
microsomal enzymes. Microsomal enzymes are important
in steroid metabolism and detoxification of foreign chemical
compounds (xenobiotics). While these are preliminary
conclusions, it is important to recall the appearance
of hepatic angiosarcoma in two species of experimental
animals at 50 ppm exposure level (rats, mice) which
would argue against a metabolic carcinogenic threshold
at 50 ppm and higher exposure levels.
9 The evidence presented in these studies suggests
alternative metabolic pathways for vinyl chloride
resulting in metabolites of perhaps differing toxicity.
However, the saturation of the presumably safer pathway
by etheno"),(and,conceivably by other substances as well,
i.e. drugs) argues that the "distinction" between
pathways may not be well defined and that under certain
conditions even relatively low exposures might be
shunted through the more toxic pathway. Furthermore
due to genetic variability, some individuals may
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. - - ' , _ «•1'
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metabolize vinyl chloride predominantly through the
more toxic pathways. In this regard, it would be
premature to conclude, based upon current evidence,
that an acceptable exposure to vinyl chloride can be
defined in terms of alternative metabolic pathways.
Vinyl chloride has been found to be excreted as '-hydroxycysteine,
suggesting metabolic transformation via an expoxide intermediate. The elimination of
xenobiotics by the formation of epoxide, followed by conjugation with
thiol containing compounds is found in the metabolism of a number of
carcinogenic compounds, as will be discussed below.
Since vinyl chloride has is a rather simple chemical structure with limited
capacity for metabolism by complex pathways, it appears to be a good
model compound for use in studies on the mechanism of chemical carcinogenesis
P. L. Grover, P. Sims and their co-workers have tested a number of
carcinogens for jm vivo and j_n vitro formation of epoxides, which have
cS, ^ 9 - 3 3
been shown to be alkylating agents of nucleic acids and proteins.
They have presented evidence for formation of epoxides for a number of
carcinogens including pyrene,34 btnzo[c]Dyrene 34 phenanthrene, 35
benz[a]anthracene35 and dibenz[a,h]anthracene. ^35^ Epoxides of
polycyclic hydrocarbons have been shown to be mutagenic to J2 bacterlODhage,
37 J '6 no
to bacteria, to Drosophila sp. and to mammalian cells.
They also produce malignant transformations of cells in culture
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Another possible mechanism of cancer induction by chemicals is via
decreased protection against the deleterious effects of free radicals.
Non-protein thiols are known to afford protection against free radicals.
However, these thiol containing compounds can be
reduced by the formation of mercapturic acid conjugates of
epoxides from reaction with glutathione.
29
Hefner et.al also reported a decrease in serum non-protein
thiol compounds after exposure of rats to vinyl chloride. This can be
related to the dangers of n.ultiple exposure to compounds related to
vinyl chloride in the same manner as for the epoxide mechanism. Indeed,
this mechanism is only a variation of the epoxide mechanism, however,
in this case free radicals are the final cause of damage, whereas in
the epoxide mechanism, reaction of epoxide with DNA or protein is the
deleterious step. A large literature also deals with the
formation of mercapturic acid derivatives of epoxides from reactions
witn giutatmone. /\ review of postulated mechanisms of carcinogenicity
of vinyl chloride and structurally related compounds has been presented
by van Duuren a
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It would be ideal to suppose that a screening procedure for car-
cinogenic chemicals could be developed on the basis of analysis of
tissue from experimentally exposed animals for epoxides or mercapturic
acid derivatives. The concentration of these materials found at
various exposure levels could theoretically be used as a risk index.
However, discrepancies in the relationship of these derivatives to
carcinogenesis preclude any such simplistic approach. The data herein
alluded too does, however, indicate that such an approach may be possible
in the future if research pertinent to the basic mechanisms of chemical
(41
carcinogenesis is supported. This research should optimistically result
in answers that would allow evaluation of the carcinogenic hazard of a
large number of existing environmental pcllutants as well as analysis of
new synthetic chemical compounds prior to their ubiquitous distribution
in the environment.
•7
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7.1.0 Aaaitional Toxicological Concerns ly'i CITE
7.1.6.1 Toxicity of Polyvinyl Chloride
The free radical content and the level of residual vinyl chloride
monomer of PVC resins and plastic end products could affect their
toxicity including potential for carcinogenic activity. Volkeimer
reported particles of polyvinyl chloride up to 70 microns in diameter
transported and deposited throughout the tissues of experimental
animals. The combination of these two observations along
with the possibility for population exposure to polyvinyl chloride
such as perhaps through erosion of PVC pipe and the wide use of
flexible plastic materials containing leachable materials indicate
the necessity for further study in this area.
7.1.6.2 Toxicity of Pyrolytic Products of PVC
Another potential problem area related to vinyl chloride is
the composition and toxicity of products produced by incineration of
PVC. Again this is a potentially widespread opportunity for general
population exposure to other hazardous materials. Disposal of PVC by
incineration is a common practice, however, little data is available on
the toxicology of pyrolytic products.
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7 2 THRESHOLD LIMIT VALUES
Although occupational health studies began in 1930, there were
essentially no reports of possible systemic effects or serious health
adversities associated with polyvinyl chloride production and/or
exposure to vinyl chloride monomer (VCM) until 1949. Chronic
"epithelial" hepatitis was diagnosed in Russian resin fabricators
(9)
engaged in processing polyvinyl chloride resins. The possible
etiological agents listed included primary ingredients used for
polymerization, compounds released from the resin during processing and
plastisizers. It is noteworthy that the possibility of potential health
hazards from exposure to residual materials released from
polymer resins was suggested more than twenty five years ago. In the
absence of chronic investigations during this period, the low
acute toxicity and the apparent lack of evidence of adverse health
effects from previous occupational experience^ threshold limit value of
500 ppm (1300 mg/m ) time-weighted average was established in 1959 by the
American conference of Governmental and Industrial Hygienists (ACGIH) as
the industrial hygiene standard for vinyl chloride in the United States.
The non governmental standard was apparently based solely upon fire and
explosive hazards that are possible at a minimal level of nercpnt (?c,000
opm) bv weight of vinyl chloride in air.
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The results of acute toxicity studies, which were the order of
the day in the early years of vinyl chloride and polyvinyl chloride
production, provided evidence of pulmonary congestion (edema) with
dan,age noted in the liver, kidneys-and tracheal epithelium
coiuonntent with narcotic effects associated with lnqh exposure
le\els of short duration Advancements in toxicological protocols and the
state-of-the-art of biomedical research alono with the evidence of orqan
oa-aoe ."M ic effect? observed under acute exposure conditions led
:o :ne cironic Jow le\eU inhalation studies of Torkelson. Oven and
, 1 ; \
¦\» he in 1 oased on observations in several species of experi-
er 1 > inat induced evidence of liver and kidney pathologv at
fe T'-res-iold Iru w3l.;e v3iV dpi > and the absence of these effects at
— o i i ov. i 11c" c ror tris of investigation, these authors recommended
the
^f\-noe i nc.-strid 'v.oiene standard. Those recommendations made in
•'Cl Ivitv'c occupational vinyl chloride exposures to less
u t ."'pi v.lth .5 tn e-weighted average not to exceed 50 pppi in air
of tne workrocr environment
. ne Subacute studies of Lester. Greenberg and AdaiiQ^ed the authors
...jti'S f.-: v.ere essentially contradictory to those of Torkelson,
w .='"-.-'"c - . u = ^?i'.e increased liver weight and slight liver
"c cc, cbser1. ec in tneir e>.peni"ental animals On the
" fese .-r- eve1' cbser\=ticns ?t higher dosaaes
ffter exccsure reriods, these authors recommended
fe ex1?:!:'; 5TT onr threshold lint value
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The Committee on the Threshold Limit Values of ttie Artrerican
Conference of Governmental and Industrial Hygienists (ACGIH) considered
the evidence presented in these two conflicting reports and chose to
change the industrial hygiene standard for vinyl chloride from a 500
(TWA)
ppm maximum time-weighted average/value to a 500 ppm ceiling level for
industrial exposure.
Along with growth and expansion in production and use of polyvinyl
chloride resins, the workforce in ^is industry increased accordingly.
In time a unique occupational health problem appeared involving those
workers engaged in cleaning polymer reactor vessels. Vinyl chloride
disease or acroosteolysis was first reported in
9
1966. This disease involved a progressive skeletal deterioration
of the fingers accompanied by interference in peripheral nerve response
and diminished blood circulation (Raynaud - like syndrome). While other
reports have appeared in subsequent years, occupational acroosteolysis
in PVC reactor cleaners has been well documented by large scale
1 Q
epidemiological studies conducted between 1969 and 1972. Since
this adversity was apparently restricted to those individuals exposed to
exceptionally high levels of gaseous vinyl chloride and the response
with PVC resins
associated more with direct dermal contacts it appeared that the
processing of PVC resins did not involve a health hazard of sufficient
severity to warrant adjustment of the industrial hygiene standard.
Furthermore, available standard textbooks and review articles have stressed the
of
safety / polymer processing and noted only a minimal risk of narcosis associated
with inhalation of vinyl chloride vapors. 47-50
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Important studies regarding occupational exposure to vinyl chloride
that were influential in adjusting permissible exposure levels were
those of Baretta, Steward and Mutchler6
44
and Kramer and Mutchler- These investigations
involved determining levels of vinyl chloride in the air of the work
area and correlating them with results of a systematic multiphasic
screening of employees using a variety of clinical parameters. The mean
concentration of vinyl chloride in the work-place air in these studies
was found to be 160 ppm with a range of 30 to 170 ppm. Vinylidine
chloride was noted as a co-contaminant at a level of 5 ppm. While no
difference was observed in blood pressure, hemoglobin levels, electrocardio-
grams nor was there evidence of morphological anomalies
(acroosteolysis), there was adequate indication of some degree of liver
damage among PVC employees at TWA exposures of 300 ppm. These observations
led the investigator to conclude that there was a definite risk of liver
damage at vinyl chloride levels of 300 ppm time-weighted average (in
the presence of 5 ppm of vinylidine chloride)
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w *» ^
The second adjustment of the industrial hygiene standard to a TWA
of 200 ppm was apparently influenced by evidence of human liver dysfunction
and the availability of monitoring data regarding levels of vinyl chloride
in air of at least one PVC production facility. -44,46 Although Torkelson
et al. had reported slight liver damage in experimental animals exposed
1 o
to 200 ppm of vinyl chloride in 1961, these observations were
apparently not fully considered until a decade later.
Due to the increasing incidence and concern regarding
acroosteolysis, experimental studies had been undertaken to develop an
animal model for elucidating the pathogenesis of this and other adverse
effects observed in humans exposed to high levels of vinyl chloride by Viola
2 20 ^
et al. in 1970 and 1971. "" ' In the course of these acute studies
carcinoapnic effects were observed and
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presented in 1970 with a later full detailed publication
of the observations in 1971.
Althouqh deficiencies in experimental design were noted
with regard to those suitable for carcinogenic investigations, there was
sufficient evidence presented that warranted further study. Subsequent
investigations were initiated in Europe and in the United States using
4,5
lower exposure levels and purer compounds. Preliminary results from these
efforts confirmed the carcinogenicity of vinyl chloride in several
species of experimental animals, a dose-response dependency of tumor
incidence was observed, and positive effects detected at exposure
3,4
levels down to 250 ppm.
While carcinogenic effects of vinyl chloride were noted at dosages
close to permissible industrial exposure levels (TLV: 200 ppm), there
was equal concern regarding the type of tumors identified and not observed
2
at hiqher exposure levels in the earlier studies of Viola et al. in
0ue Due to the history of liver dysfunction in PVC employees and
in chronic experimental animals observed earlier particular concern was
3,4
aroused by the appearance of liver angiosarcoma in experimental animals-
Increasing interest in vinyl chloride followed the findings that
4 employees at
this a PVC plant had died of either liver angiosarcoma, a
rare form of human liver cancer, or other liver cancers of unknown types
from 1968 to 1973^. A fifth individual died in late 1973 of cirrhosis of
i i &
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the liver. Investigation of the exposure history of these
individuals revealed that the deceased employees had an average exposure
of 19 years to vinyl chloride and ten years to vinylidene chloride.
These workers had been engaged in operations where vinyl chloride
^concentrations may have greatly exceeded the 1972 Threshold Limit Value
Or (200 ppm).
^ In view of these considerations and results from on-going toxicological
Q— • j
studies, government officials pursuant to the statuatorv reouirements nf the
-cupational safety and health legislation of 1970 promulgated an
« emergency standard for
1
industrial exposure at 50 ppm in early 1974 as efforts to determine the
5 I
scope of the occupational problem were accelerated. Results of the
American and European toxicology studies soon revealed the induction of
liver angiosarcoma and other tumors at a 50 ppm exposure level of vinyl
3-5
chloride. Industrial epidemiological investigations identified
additional cases of liver angiosarcoma among American and European
PVC workers. An occupational standard of 1.0 ppm (or detectable
levels) was then proposed by the Occupational Safety and Health
Agency, U. S. Department of Labor as an industrial exposure standard
for vinyl chloride in American industrial facilities. ^
Subsequently, a permanent 1 ppm time-weighted average occupational
standard (8 hours per day; 5 days per week) with a peak 5 minute
excursion not to exceed 5 ppm has been promulgated.
Angiosarcoma of the liver is an extremely rare tumor in the
general population of the United States. The incidence of angiosarcoma
among employees involved in the manufacture of monomeric vinvl rhlnrine
and polyvinyl chloride resins substantially exceeds the estimated
national incidence level. During the course of retrospective analysis
of various tumor registries, several community cases of liver
angiosarcoma were discovered. Althouqh the general public has been expose'
• 1
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to vinyl chloride thorugh other exposure routes (e.g. aerosol sprays),
particular concern has been expressed regarding community cases of
liver angiosarcoma among those with residence situated near VC/PVC
production plants and resin fabricating facilities. Questions have been
raised regarding exposure of the more than 700,000 workers employed
in fabricating PVC resins containing residual monomeric vinyl chloride
as well as the degree of community exposure surrounding these
plants. It is noteworthy that the first reported occupational health
problems associated with polymer processing involved workers engaged
in fabricating resins into plastic products. Vinyl chloride
has been detected in the ambient air near vinyl chloride and
polyvinyl chloride production sites.
The appearance of liver angiosarcoma in experimental animals serves
to underscore the predictive value of well designed and executed loxicoloqical
studies in identifying potential health hazards to man. While it
is always a curiosity to ponder speculations on a retrospective basis,
had adequate studies been performed at an earlier date, the problems
exposure
associated with vinyl chloride/may well have been identified before
human cases of liver angiosarcoma among PVC workers had occurred.
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Irish, D.D. Halogenated Hydrocarbons: I Alfpratic. in: industrial
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Marsteller, H.J., W.K. Lelbach, R. Muller, and P. Gedigk. Unusual
Splenomegalic Liver Disease as Evidenced by Peritoneosocpy and
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Torkelson, T.R., F. Oyen, and V.K. Rowe. The Toxicity of Vinyl
Chloride as Determined by Repeated Exposure to Laboratory Animals.
Am. Ind. Hyg. J. 22:354-361, 1961.
14. Cornish, H.H. Problems Posed by Observations of Serum Enzymes
Changes in Toxicology. CRC. Crit. Rev. Toxicol. 1^:1-32, 1971.
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Correlation Between Serum Enzymes, Isoenzymes Patterns and Histologi-
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16. Grice, H.C. The Changing Role of Pathology in Modern Safety
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Harmone Dependent Association of Membrances with Polysomes. Nature,
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18. Roobol, A. and B.R. Rabin. The Binding of Polysomes to Smooth
Membranes of Rat Liver by Steroid Hormones and Extracts from Either
Rough Endoplasmic Reticulum or from Polysomes of the Opposite Sex.
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19. Pi tot, H.C. Endoplasmic Reticulum and Phenotypic Variability in
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20. Viola, P.L. Pathology of Vinyl Chloride. Sixteenth International
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22. Popper, H. Alterations of Liver and Spleen Among Workers Exposed to
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23 Rad, K.S. and R.D. Recknagel. Early Onset of Lipoperoxidation in
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Bendetti, A., M. Ferrali, E. Chi ell, and M. Comparti. A Study of
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Munson, R.R., J.M. Peters, and M.N. Johnson. Proportional Mortality
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Ranning,
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V., V. Johansson, K. Ramel, and V. Wachtmeister. Mutagenicity
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Selikoff, I. J. Personal Communication, Mount Sinai School of
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Studies of the Fate of Inhaled Vinyl chloride Monomer (VCM) in Rats
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Grover, P.L. and P. Sims. Interactions of the K-Region Epoxides of
Phenanthrene and Dibenz ua,h] Anthracene with Nucleic Acid and Histone
Biochem, Pharmacol. 1^:2251-2259, 1970.
Grcver, P.L. and P. Sims. Enzyme-Catalysed Reactions of Polycyclic
Hydrocarbons and Deoxyribonucleic Acid and Proteins In Vitro. Biochem
J. 110: 159-160, November 1968.
Grover, P.L., J.A. Forrester, and P. Sims. Reactivity of the K-Region
Epoxides of Some Polycyclic Hydrocarbons Towards the Nucleic Acids and
Proteins of BHK 21 Cells. Biochem. Pharmacol. 2(3:1297-1302, June 1971
Kuroki, T., E. Huberman, H. Marquardt, J.K. Slekirk, C. Heidelberger,
P.L. Grover, and P. Sims. Binding of K-Region Epoxides and Other Deri
vatives of Benz [a_j Anthracene and Diznez [a,h] Anthracene to DNA, RNA
and Proteins of Transformable Cells. Chem. - Biol. Interactions
4:389-397, 1971/1972.
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35. Grover, P.L., A. Herver, and P. Sims. Formation of K-Region Epoxides
as Microsomal Metabolites of Pyrene and Benzo [a] Pyrene. Biochem.
Pharmacol. 21_:2713-2726, November 1972.
36. Grover, P.L., A Herver, and P. Sims: Epoxides as Microsomal Metabolites
of Polycyclic Hydrocarbons. FEBS Letters 18:76-80, January 1971.
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Mutagenicity of Mammalian Cells of Epoxides and Other Derivatives of
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Their Mode of Action in: Biological Effects of Alkylating Agents.
Ann. New York Acad. Sci. 163:633-651, 1969.
42. Stoltz, D.R., L.A. Poirier, C C. Irving, H.F. Stich, J.H. Weisburger
and H.C. Grice. Evaluation of Short-term tests for Carcinogenicity.
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7- 2 -N
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Kramer, C.G. and J.E. Mutchler. The Correlation of Clirh'cal and
Environmental Measurements for Workers Exposed to Vinyl Chloride.
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to Vinyl Chloride Vapor: Breath Analysis and Continuous Air Sampling.
Am. Ind. Hyg. Assoc. J. 30:537, 1964.
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May 10, 1974.
1 - 2 - 15
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i. n.- r ;
7.3 HUMAN EFFECTS ',J' QUO i E Or, 1,1 i
To date most of our knowledge of undesirable effects associated with
vinyl chloride exposure in man comes from occupational situations. These
effects include an increased risk of cancer at multiple organ sites includ-
ing angiosarcoma of the liver, an almost invariably fatal form of liver cancer.
Liver angiosarcoma is extremely rare among the general population) but has
been observed among workers with exposure to vinyl chloride.
It is recognized that
angiosarcoma observed today in workers exposed to vinyl chloride was qenerally,
though not exclusively, the result of very high occupational exposures received
many yeara ago. The latent period for angiosarcoma of the liver has
been estimated at between 15-20 years following onset of exposure although
1 >2
individual cases may occur after shorter or longer latent periods.
This long latent period suggests that the full impact from past vinyl
chloride exposure among workers may not be realized until many years
from now since the greatest number of workers have had onset of exposure in the
last decade. For example, of the 25 known occupationally reported cases of live
angiosarcoma, information as to date of diagnosis or death, where available,
indicates that only 2 of 22 cases died prior to 1965 and that 14 of 22 cases had
died or were diagnosed in 1970 or later.2 Accordingly estimates of cancer risk
from vinyl chloride based upon data available today may well understate the
magnitude of this problem. In this regard, increased awareness and improved
diagnostic procedures may in part also contribute to future increases in reported
cases of liver angiosarcoma.
To date surveys have uncovered 15 cases of occupationally reported liver
angiosarcoma in this country.2 Of these cases. 14 have been among workers
PVC polymerization plants and one case involved an accountant employed at
-------
DRAFT
DO NOT yUOTF CR CITE
a vinyl cloth plant. At least 13 of these cases have been
comfirmed as angiosarcoma of the liver by pathologists at the National Cancer
3
Institute. In addition to these 15 U.S. cases, 10 occupational cases of liver
angiosarcoma have been reported from European countries, 7 among workers in
the PVC polymerization industry and 3 among non-polymerization workers. A
summary of these reported occupational liver angiosarcoma cases is shown in
Tables 7.3.1 and 7.3.2.
As indicated in these tables, the latent period from onset of initial
exposure to age at diagnosis or death in all known instances is 10 years or
greater. Similarly the years of exposure among these individuals preceding
development of clinical disease is with one exception also in excess of
10 years. This one exception may, however, be important and involves a case
in which there was an established occupational exposure history of only 4
years' duration. This case suggests that disease may, in certain instances,
develop after relatively brief durations of occupational exposure to vinyl
chloride or, alternatively, that other factors besides vinyl chloride may
have been involved. These cases represent all currently known occupationally
reported liver angiosarcomas., A reported case of liver
angiosarcoma in an employee at an electrical insulation plant in Connecticut
upon re-examination by pathologists at the National Cancer Institute,
4 5 6
was not considered to be liver angiosarcoma.
With respect to the general population, at one time there were believed
to be 3 reported cases of liver angiosarcoma among individuals who had
resided in the vicinity of industrial vinyl chloride emission sources. A
review of these cases by pathologists at the National Cancer Institute has
confirmed the diagnosis of liver angiosarcoma in two of the three instances. One
7 J -2-
-------
Case
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
DRAFT
T K, 7 11 00
Table /.3.1
LIVER ANGIOSARCOMA CASES AMONG
VC POLYMERIZATION WORKERS2
Date of Years after Years of Age at
Country Death First Exposure Exposure Diagnosis
West Germany
1969
11
11
39
United States
A1 i ve
12
12
45
United States
1971
14
13
37
West Germany
1971
14
14
40
United States
1968
15
15
44
United States
1961
15
15
41
United States
1968
17
17
54
United States
1969
18
4
41
Sweden
1970
19
18
43
United States
1969
20
15
50
United States
1964
20
18
52
United States
1973
22
16
51
Norway
1972
22
21
56
United States
1970
23
23
60
United States
1968
24
18
45
United Kingdom
1972
26
20
71
United States
1973
28
28
59
United States
A1 i ve
29
17
43
United States
1974
30
30
52
Czechoslovakia
Awaiting Details
Czechoslovakia
Awaiting Details
l.t "3-
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CRAFT
co f:;r quotc or cife
Table 1.2.2
Country
LIVER ANGIOSARCOMA CASES AMONG
NON-VC POLYMERIZATION WORKERS2
Date of
Death
Years after
First Exposure
Years of
Exposure
Age at
Diagnosis Notes
United States 1973
West Germany
United Kingdom 1970
Sweden
1972
14
24
27
11
23
47 Accountant at
vinyl cloth
plant
43 Filled pesti-
cide cans
with VC
propellant
55 Vinyl cloth
pi ant
61 VC monomer
production
plant
7 3 -4-
-------
case of a woman in Buffalo, New York that was originally believed to be
liver angiosarcoma has now been rediagnosed as an anaplastic carcinoma
rather than a sarcoma.^ The two other cases ,^/Wom Connecticut, represent
confirmed angiosarcomas^'^'^ but these cases are not identical in all
I
respects to the pathology which has been observed among PVC polymerization
workers. ' ' The implications of these dissimilarities between community
and occupational cases are not fully understood. Angiosarcomas of the liver
resulting at lower exposure doses may not be charac- ~~
terized by all the pathologic findings seen in the PVC workers who in general were
exposed to high doses of vinyl chloride. On the other hand, the possibility
must also be considered that these two Connecticut community cases were un-
related to vinyl chloride exposures. The fact that Connecticut has one of
the finest tumor registries in this country may be important since other
states with less adequate followup procedures would not be able to readily
identify suspect community cases of liver angiosarcoma. Further the clustering
of these 2 community cases and the above mentioned accountant around VCM emission
sources in Connecticut raises the possibility of a causal relationship.
these community cases, one was a 73-year old man who had lived
his entire life within 2 miles of an electrical products factory which pro-
cessed electrical insulation made of PVC. The other was an 83-year old woman,
a housewife and retired cook, who resided for 35 years within % mile of the
vinyl products plant at which the above-mentioned accountant was employed.4
It should also be noted that both community cases lived in excess of 70 years.
In contrast, over half of the 25 reported occupational cases mostly at high levels
were
of exposure/either diagnosed or had died at ages 50 years or younger and only one
case lived in excess of 70 years. These community cases may reflect an increase in
latent period at low levels of exposure as has been suggested in animals studies.9
As a result of the reported cases of liver angiosarcoma among vinyl chloride
workers, a number of studies have been conducted examining the mortality experience
of these workers and contrasting this experience with that observed in the qeneral
population.
-------
rs • • •••
!
r r. : • , „ ,
L'u '.¦til;11
Tabershaw/Cooper Associates conducted a mortality study of workers
in the vinyl chloride industry.10,11 The objectives of this study were
threefold: (1) To contrast the mortality experience of individuals
employed in vinyl chloride plants with that of the general population;
(2) To examine mortality patterns among vinyl chloride workers in relation
to estimated occupational exposure; and (3) To compare mortality patterns
among vinyl chloride workers with those for otner occupational groups.
The study population was composed of 8,384 individuals from 33
domestic plants with at least one year of occupational exposure to vinyl
chloride, including retired and terminated as well as currently employed
workers. The vital status of these workers was ascertained as of December
31, 1972 and cause of death was determined based upon available death
certificates. Observed mortality was then compared to expected mortality
based upon the United States male population accounting for age and time
of death and Standardized Mortality Ratios were computed for total mortality
and specific causes of death.
Exposure categories were defined subjectively by industrial hygiene
and safety personnel at each plant who identified those jobs and work
lcoations with the highest exposures to vinyl chloride and classified other
job categories as medium or low relative to those jobs with the greatest
exposures. This procedure was reasonable for estimating relative exposure
within a given plant but could not assure comparable exposure categories
across all plants or over time since a low exposure in past years might
be numerically equivalent to a relatively high exposure in recent years.
An exposure index was calculated for each worker as a time weighted average
7,1 -6-
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< V ^ TT
u'iwl I
cj ;«ot cl'ct: cr c.te
of exposure categories over the period of employment allowing an overall
low and a high exposure category to be defined.
Followup procedures were adequate to define the vital status for
85% of the study population as of December 31, 1372. Among the 352 workers
known to have died, death certificates were obtained for 328 workers. The
mortality calculations considered only those workers who had been success-
fully traced which assumes that the mortality experience of these workers
was equivalent to those who were not successfully traced. The median birth
year for those successfully traced was 1931 compared to 1920 for those
not traced The median year in which exposure began was 1962 among those
successfully traced compared to 1953 among those not traced. The median
duration of employment for those successfully followed was 80 months in
contrast to 44 months for those who were not traced. Thus, while those
successfully traced had about twice the duration of employment as those
not traced, those who were not traced began their employment about 10 years
prior to those for whom followup was complete. Accordingly, the mortality
experience among those not traced might have been different from that in
the study population considering the increased latent period since onset
of exposure in this group. More than half (about 60cO of the study popu-
lation entered employment in 1960 or later indicating that the majority
of workers in this study were not followed for an adequate length of time
afce," exposure beqan to assure observation of all Dotential lona tprm pffprtc.
Included among the 7,128 workers successfully traced, however, were 854
workers with 20 or more years' exposure and 1,640 workers with exposures
of 15 years or greater. The discover;/ of 1,500 workers with exposures
A/ I -7-
-------
[.¦ i.'.:t or cite
occurring up to 35 years ago -- too late to be included in the study group-
should also be noted since these workers would have provided information
as to the effect of very long exposure and long latency upon mortality,
areas in which the present study was relatively weak.
The effects of exposure index (low vs high) and duration of exposure
(less than or greater than 5 years) upon mortality as well as interaction
effects between level and duration of exposure were examined.
Based upon these calculations, the following observations were made:
-- Compared to the general male U.S. population
the overall mortality of the study population
was approximately 75% of what would have been
expected. This favorable overall mortality
frequently occurs in occupational groups even if
an industrial hazard increases the risk of death
from a particular cause, since occupatonal groups are usually younqer
and healthier than the average general population.
No specific cause of death was increased to a statistically
significant extent above what would have been expected in
a comparable U.S. male population.
Sf1R s (Standardized Mortality Ratios) for malinnant neonlasms
as a whole increased
with increasing exposure, measured by level, duration or both.
For example, 36 malignancies were observed in the high
exposure group with 5 years or more exposure compared to
26.11 expected cases. Among those with greatest exposure,
cancers of the liver (primarily angiosarcoma), respiratory
7.1 -8-
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DRAFT
DO NOT OUO'L OR CITE
system, brain, cancers of unknown primary site and
lymphosarcoma occurred more frequently than expected.
Though these findings were not statistically significaot, the authors
of the Tabersnaw-Cuuper stuuy consiuereu these findings sugoestive
of "a relationship between exposure
to vinyl chloride and increased cancer risk at multiple
sites, since the number of deaths for many cancer causes in ;.nr-
study is quite small. Accordingly, even relatively high SMR's
may not be statistically significant.
The results of a long-term mortality study of 594 chemical workers
exposed to vinyl chloride between the years 1942-1960 at the Dow Chemical
12
Company were reported. The study population was defined as production
workers at one manufacturing facility who worked in areas with potential
vinyl chloride exposure. Each job classification was assigned an expo-
sure rating of low, intermediate, or high depending upon the existing
industrial hygiene data. This is the only available mortality study in
which vinyl chloride exposures could be reconstructed using actual
air measurements. Three categories of exposure were defined based
upon estimated time-weighted average concentrations for an 8-hour day.
The low-exposure group consisted of those with TWA concentrations below
25 ppm vinyl chloride, the intermediate group had TWA exposures ranging
from 25-200 ppm, and the high group was characterized by TWA exposures
of 200-300+ ppm. Also included in the high group were those with TWA
exposures in the intermediate range but who were also exDosed to frequent
unpredictable excursions above 1,000 ppm. A fourth category of indeterminate
exposure was defined for individuals working in areas where insufficient
air monitoring data were available. A subjective evaluation suggested that
for these individuals, exposures were mostly in the low to intermediate
range.
7 3 -9-
-------
Assignment to exposure groups was determined by the highest exposure
experienced for one or more months. By this procedure, the lowest
exposure category contained only individuals with low exposure whereas
the highest exposure group included some individuals with predominantly
lower exposures. Duration of exposure was considered based upon two
categories — less than one year, and one year or longer. Accordingly,
effects of longer durations of exposure well above one year were not adequately
examined, although the impact of latent period since onset of exposure
was considered in the analysis. A number of members in this study (72)
had histories of exposure to both vinyl chloride and arsenicals. In view
of the cancer risk associated with arsenicals, the employees with arsenic
exposure were excluded from dose-response relationships related to vinyl
chloride.
Expected deaths in this cohort were determined from United States
white male mortality rates. Death certificates were obtained for 86
of the 88 individuals known to have deceased. Of the 148 individuals who
had left the company, 131 individuals were successfully traced. Among
the individuals who had worked with arsenicals and vinyl chloride, 7 of 10 deaths
due to neoplasms compared to 1.9 cancer deaths expected. No lung .'cancer
was noted in this group. .Among workers exposed to VCM but not arsenicals, observed
deaths were 91% of the expected deaths based upon the U.S. white male
population, suggesting a possible increase compared to other chemical
production workers at the same site who experience mortality rates 15-20%
below the U.S. white male population. Wo deaths due to angiosarcoma of the liver
or other liver cancers were noted in the .qroup exposed to vinyl chloride
7-1 -10-
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DRAFT
L/C not Quorr or cite
but not arsenicals. For this group as a whole, total malignancies
were less than expected; 13 observed compared to 15.4 expected.
The effect of exposure grouping upon malignancy rate was examined
for this cohort exclusive of arsenical workers. Of 163 individuals in
the high exposure group, only 27 had 20 or more years at low to high
exposure and only 19 had 10 or more years of only high exposure. Of
the 13 malignancies observed in this cohort, 9 occurred in the high-
exposure group, compared to 5.1 expected. Due to the small number of
deaths involved, this difference was not tested for statistical sig-
nificance. To examine for possible latent effects, the mortality
experience of workers with 15 or more years since onset of exposure
was studied. In this group, 9 malignancies were observed, 8 of which
occurred in the high-exposure group. Accordingly, 8 of the 9 malignan-
cies observed in the high-exposure group occurred 15 or more years after
onset of exposure. Shown in Table 7.3.3 are summaries of the results.
Based upon this study, the authors concluded that workers exposed
to vinyl chloride a.t levels above 200 ppm experience an "apparent
increase in overall malignancy rate." When exposures were kept below
200 ppm a decrease in the malignancy rate was found. Angiosarcomas of
the liver were not found at any level of exposure. Among the workers
exposed above 200 ppm TWA, the increase in overall malignancy was not
statistically significant. The authors also commented as to possible
cocarcinogenic effects of other exposures with vinyl chloride, particularly
benzene, cigarette smoking and arsenic.
7.1 -11-
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r n <\ rr
L>f\/\!~ I
CJ NOT QUOTE OS CITE
Table 7.3.3
SUMMARY OF DOW MORTALITY STUDY12
Study Population
a) Years exposed: 1 year or more
b) Onset since first exposure: No restriction
c) Size of cohort: 594, total;522 with VC exposure only
d) Number successfully followed up: 577
SMR's (excluding arsenic workers)
_0/E_
SfMR
All causes
78/85.7
91
All cancers
a)
All VC exposed
13/15.4
84
b)
Only high exposure group
9/5.1
176
-- Less than one year exposure
3/2.2
136
c)
--One year or more exposure
6/2.9
209
High exposure group with 15 years
after onset of exposure
8/3.2
250
— Less than one year exposure
3/1.3
231
-- One year or more exposure
5/1.9
263
*SMR = standardized Mortality Ratio.
7,1-k-
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DRAFT
do r::-T quote on cite
In reviewing these data, certain strengths in this study are evident,
expecially the availability of measured vinyl chloride exposures and the
successful followup of over 95% of the cohort. Several weaknesses must,
however, also be mentioned. The high exposure group was composed pre-
dominantly of individuals with a range of exposure from low to high levels.
Since onTy one month of high exposure was required to place an individual in this
group only 19 of 163 members in this group, had exposures exclusively
to high levels for periods of 10 years or more. Accordingly, though all
members in this group experienced some vinyl chloride exposures in the
range of 200-300+ ppm TWA, it is likely that this group as a whole had
TWA exposures which were, in fact, below 200 ppm when averaged over the
work histories of all members in this group. Further, the frequency
of high exposure in this group is also not known and this may be impor-
tant with respect to repair mechanisms. On this basis, increased
malignancies might have occurred among individuals with lifetime
average exposures below 200 ppm. Another weakness is that duration of
exposure to vinyl chloride was not adequately considered in this analysis.
For example, 7 of the 9 individuals in the high exposure group with
malignancies had been exposed to vinyl chloride for more than 10 years,
but only 66 of 163 individuals in the high exposure group had 10 years
or more exposure to vinyl chloride. In this regard, reanalysis of the
data for those with only 10 years or more exposure might have re-
sulted in greater increases in observed compared to expected malignancy
rates.
Monson et. al. conducted a proportional mortality study among workers in a
vinyl chloride monomer plant in Calvert City, Kentucky and among workers
13 14
in a vinyl chloride polymerization plant in Louisville, Kentucky. '
Death certificates were used as a source of cause of deaths and certificates
7.1 -13-
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DRAFT
DO r:3) Q'JOfE CR CITE
were obtained for 142/161 white males employed at these plants who were
known to have died. When death certificates were not available, cause
of death as recorded in company abstracts were used.
Causes of deaths for these 161 individuals were tabulated covering
the period 1947 through 1973 and these were compared with the expected
distribution of deaths as calculated from proportional mortality ratios
for United States white males accounting for age and time of death.
Since mortality patterns among workers in both plants were similar,
these groups were combined for purposes of data analysis. Overall, a
statistically significant 50% excess in deaths due to cancer was observed.
Five cases of liver angiosarcoma were identified in this study in addition
to cancers (one each) of the gall bladder, common bile duct and an
unspecified case of liver cancer. All told,a 900% excess in cancers of
the liver and bilary tract was observed. If the cases of angiosarcoma
were excluded from this analysis, a 275% excess in these cancers was
observed. Five cases of brain tumors were also found as were 13 cases of
lung cancer. These represented 320 and 60% excesses above
the expected frequency of these cancers, respectively. A 100% excess in
deaths due to suicides was also noted.
In addition to these overall cancer excesses, an increasing trend of
cancer deaths with time was observed. No excess deaths due to cancer were
observed prior to 1965. However, in the period 1965-69 about a 50% excess
in total cancers was observed and in the period from 1970 and later a 100%
excess in total cancer deaths was found.
7.1 -14-
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nn,*FT
\J j I > ^ ' y o ^ i .- ^ 1 ^ *-
This trend is generally consistent with the clustering in recent
times of reported occupational cases of liver angiosarcoma.
These data infer that at least two other forms of cancer, lung and
brain, in addition to liver cancer, are increased among vinyl chloride
workers. The present analysis did not examine the absolute risk of
death in the study population, which conceivably could be less than in
the general population. However, the observed excesses in specific
was considered by the authors to
cancers combined with the time trend for all cancers' suggest a relation-
ship between exposure to vinyl chloride in the work environment and
cancer at multiple sites.
Nicholson et al. utilized Union and Company records to identify a
cohort of 257 individuals each with a history of occupational exposure
to vinyl chloride in a polymerization plant for at least 5 years
15
subsequent to 1946. This cohort included all individuals employed
in this plant during the period 1946-1963. The mortality status of these
individuals was evaluated from the tenth anniversary of their employment
through April, 1974. The minimum 5-year exposure criterion was established
to focus upon the effects of significant durations of exposure. Beginning
observations after only 10 years or more since onset of first exposure
was meant to emphasize the possible long term effects of vinyl chloride.
The majority of individuals in this cohort, however, were exposed to
vinyl chloride for a period of 20 years or under.
This cohort represents a relatively young group since over half of
the men were under age 37 when they entered the cohort. Over half of the
men are presently employed in the PVC production facility though not all
in locations with vinyl chloride exposure.
7,1 -l*-
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OnrT
do ;;or quote ea cit
Of the 257 individuals in this cohort, 255 or 99% were successfully
traced and their current health status evaluated. The majority of these
men were directly employed in production although maintenance men and non-
production workers were also included. Thus exposures varied
considerably among study subjects. Unfortunately no measurements of actual
exposures were available and no effort to consider exposure in the data
analysis was made except for the exclusion from this cohort of those
individuals employed exclusively as plant guards or outside the reactor
and dryer buildings. Over half of the workers, however, reported experien-
cing symptoms of dizziness, headache or euphoria during work periods and
14 had experienced episodes of loss of consciousness. Accordingly, the authors
concluded that peak
vinyl chloride exposures may often have exceeded 1,000 ppm and may have
occasionally approached 10,000 ppm in this production facility.
Included among the 24 deaths identified in this cohort were 3 confirmed
cases of angiosarcoma of the liver. Despite the limited observations,
the excess in total mortality and in deaths from cancer in this group
(presumably compared to the white male U.S. population) is unusual in view
of the relatively short period of followup. These preliminary findings
suggest an excess in all deaths of 25% and a 131% excess in all cancer
deaths though in neither case did these excesses reach statistical signifi-
cance. In addition to liver angiosarcoma, one brain cancer and 2 lymphomas
were observed, causing the authors of this study to consider, in view of thp
rarity of these cancers, a (Jussible reldlionsnip Detwcen exposure and effect.
A study of mortality and morbidity among current and past employees
at two vinyl chloride polymerization facilities was conducted by the
7.1 -16-
-------
DRAFT
iv m.v Quoic or ;fe
National Institute of Occupational Safety and Health.2 The criteria for
selection of these study facilities were in order of decreasing priority:
(1) involvement in the polymerization of vinyl chloride for at least 15
years; (2) existence of a siizable work force; (3) location in a state
where vital status ascertainment would be facilitated; and (4) existence
of an inhouse medical program.
Since cancer often takes many years to become clinically evident,
the study population was restricted to individuals with 5 or more years
employment and at least 10 years since onset of employment in depart-
ments directly involved in polymerization of vinyl chloride. The study
population consisted of 930 white males. Followup of study members
was endeavored from the time of employment termination to December 31,
1973. Unfortunately, 285 individuals (31%) were not successfully followed
up, and it is unknown how the mortality experience of these people com-
pared to those who were successfully traced. All individuals not
successfully traced were considered to be alive and were included in
the analysis, thereby making any findings of increased mortality in this
study cohort a conservative estimate of risk. Comparisons between observed
risk of death in the study population and expected risk based upon mortality
rates for the general white male population of the United States were made.
Measurements or estimates of previous exposure levels to vpm were not incited
in this study--an important limitation.
A total of 109 deaths were observed among these polymerization workers
compared to 105 which would have been expected. Though this difference
i -17-
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DRAFT
DO f-rOr QUOTE CR CITE
is not statistically significant, it is still noteworthy since most
occupational groups have a favorable mortality experience compared to
the general population. Any deaths in the 31% lost to followup would,
of course, have increased the observed number of deaths even more. An
evaluation of specific causes of death indicated that, except for cancer,
causes of death in the study group did not differ from those expected
in the general population. However, a statistically significant (P <0.01)
57% excess in cancer deaths above that which would have been expected was
observed. This excess could increase as the status of those lost to
followup is ascertained. Within this cancer category, excess deaths were
not limited to any single organ system, excesses being observed for
cancers of the respiratory system, blood forming tissues, and the brain
and central nervous system. Deaths due to liver cancer in this population
were almost 12 times above the expected number, and brain cancer
deaths were increased fivefold. These latter contrasts were statis-
tically significant (P <0.01 and P <0.05, respectively). It is not
stated whether excesses in liver cancer besides angiosarcomas were observed.
The majority (25/31) of observed cancer deaths in this study population
did not occur until at least 15 years following first exposure to vinyl chloride.
7.3.4
Shown in Table / is a comparison of the NI0SH mortality study with other
mortality studies conducted by Tabershaw/Cooper Associates, the Mount Sinai
School of Medicine, the Dow Chemical Company and Harvard University. It
is evident that the results of all studies are reasonably consistent and
together suggest an overall excess in cancer mortality among workers
exposed to vinyl chloride for long durations. Both the NI0SH and Mt. Sinai
7.1 -18-
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LU
C_5
cr
o
LJ
Table 7.3.4 A COMPARISON OF MORTALITY STUDIES AMONG VINYL CHLORIDE WORKERS
<3! o
C2) &
i—
CD
O
CD
Comparison
Tabershaw/n
Cooper IU,M
Study
Dow
12
NIOSH'
Mt Siria
I5
Harvard
13,14
Number of Plants
Study Population
a) Yrs. exposed
b) Onset since
first exposure
c) Size of cohort
d) No. successfully
followed up
e) No. of deaths
SMR's or Relative Risk
All causes of death
All cancers
Multiple cancer sites
suggested
Angiosarcoma of the
liver found
33
1 yr or more
No restriction
8,384
7,128
(85%)
352
75
110 (total )
114 (only
those with 5
yrs or more
exposure)
Yes
Yes
1 yr or more
No restriction
522
505
(97%)
88
91
84 (total)
250 (only those
with high expo-
sure with at
least 15 yrs
after onset of
exposure
Yes
No
5 yrs or more 5 yrs or more No Restriction
At least 10 yrs
930
645
(69%)
109
103
157**
At least 10 yrs No Restriction
257
255
(99%)
24
126
231
Yes
Yes (?)
Yes
Yes
* Statistically significatn at p <0.05
** Statistically significant at p <0.01
161
150*
O
o
o
v ^ "2
Yes c--
o
-r"l
r-<
Yes
m
-------
Draft
DO NOT QUCTL fW CITE
studies which employed the same study criteria also suggest a disfavorable
overall mortality experience among these workers, but neither comparison
shows statistically significant differences in this regard. It is note-
worthy that in each study, workers exposed for 5 or more years to vinyl
chloride had greater than expected frequencies for all cancers ranging
from 41-150% excesses; however, in only two studies were these excesses
statistically significant at the 0.05 level or lower. The close similarity
of these studies to the animal toxicology data also showing multiple
organ involvement in carcinogenicity is worthy of note.9
In evaluating these observed mortality effects among vinyl chloride
workers it must be recognized that the workplace situation may include
exposures to other carcinogens and/or liver toxins in addition to vinyl
chloride and that any one of these may have contributed to the observed
effects. While this situation makes it difficult to draw final conclusions
with regard to the role played by vinyl chloride in the development of
liver cancer it is noteworthy that toxicologic studies in mice, rats and hamsters
have observed liver angiosarcoma following inhalation exposures to vinyl
chloride at concentrations of 50 ppm and higher.5'16'17 The liver angio-
sarcoma lesions observed in these animal studies combined with the observations
in industrv stronqlv implv that vinvl chloride is related to liver angiosarcoma
in man.
Most, but not all, cases of liver angiosarcoma to date have been
detected among workers involved in the production of polyvinyl chloride
from the vinyl chloride monomer. These workers may have been exposed to
concentrations of vinyl chloride monomer in excess of the old threshold
limit value (200 ppm TiJA, 500 ppm ceiling) at some time in the past and it
could be argued from these data that vinyl chloride does not produce liver
7, > - 20-
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DRAFT
00 NOT QUOTE CR CITE
angiosarcoma in man except at these higher (> 200 ppm TWA) exposures.
In support of this position is the fact that liver angiosarcoma
has not been reported to occur in workers employed in Southern and
Southwestern United States VCM and PVC production plants. These
facilities are frequently located outdoors and hence would result in
lower levels of exposure to VCM than found in indoor plants. Further,
the possibility must be considered that additional chemicals other than
vinyl chloride, such as perhaps other halogenated hydrocarbons or trace metals,
may have contributed to liver angiosarcoma in some workers.
On the other hand, a relatively small number of workers were employed
in the VC/PVC production industry in the 19401s and consequently a
sufficiently large number of individuals at all plants may not have
been exposed for adequate durations to allow detection of effects in
a disease with a long latent period. An adequate period of time may also
not have elapsed since the onset of exposure to permit the emergence of
effects among workers from all plants making VC or PVC at this point in time.
Most plants in which liver angiosarcoma has not been observed began
1 ft
production of VCM or PVC in 1950 or later.
_ r» > k
7. * -
-------
LWW' I
Accordingly, the limited DO NOT QLIQ1 L DR CITE!
period of observation following onset of exposure among most vinyl
chloride workers combined with the long latent period generally required
before clinical evidence of disease is considered the most likely expla-
nation for failure to observe liver angiosarcoma in workers employed at
all plants particularly those in the Southern and Southwestern United
States. Of 12 Southern or Southwestern VCM plants for which data are
18
available, only one was in operation prior to 1950. Of 8 Southern or
Southwest PVC plants currently in operation for which there are available
18
data, only one was in operation prior to 1950.
With respect to levels of vinyl chloride exposure required to produce
liver angiosarcoma, most, but not all, occupational cases reported to data
have occurred among PVC workers and consequently may generally have involved
TW®. exposures in excess of 200 ppm with peak excursions in excess of 1,000
ppm. The most definitive evidence for past exposures among these workers
comes from actual 8-hour average air measurements ranging from 120-385 ppm
and excursions of 2,000 -4,000 ppm among highly exposed PVC workers at the
Dow Chemical Company from 1950-1959. Evidence peak exposure
excursions in excess of 1,000 ppm among PVC workers in past years is also
derived from the frequent reports of neurological symptoms among such workers.
Existence of odors attributed to VCM for much or part of the workday at these
plants would tend to support these observations since the odor threshold for
20
vinyl chloride is believed to be 250 ppm or higher.
Reports of liver angiosarcoma among workers exposed'to VCM but not
involved in the production of PVC, however, including that of an
accountant in a U.S. vinyl cloth plant wnulH tend to araue that at
least for some individuals, liver angiosarcoma may occur at much lower ex-
posures than encountered among PVC workers. Cases of liver angiosarcoma
are reported in a worker employed at
7.1 - 1 ^
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DRAFT
DO NOT QUOTE 0!f CITE"
a VC monomer plant in Sweden and in a worker from England employed at
2 19
a vinyl cloth plant. Data from the Dow Chemical Company show TWA
exposures at monomer plants in the years 1973-1974 to generally be under
10 ppm although short-term exposures in excess of 100 ppm have been re-
ported. A survey by the National Institute of Occupational Safety and
Health has shown VCM levels in fabricating plants to range from 1-12
21
P*3111 ' In the case of workers at fabricating plants, vinyl
chloride exposures may result in part from release of trapped monomer in
the PVC during processing and/or from inhalation of PVC dust containing
entrapped monomer. While it is difficult to reconstruct exposures to
vinyl chloride in these instances, it is likely that exposures for the
workers involved in the fabrication process are considerably less than those
for workers involved directly in the production of the monomer or the
polymer.
In addition to the carcinogenic effects of vinyl chloride, a consider-
able body of evidence has become available related to non-malignant, effects
in man including reactions of the liver to vinyl chloride. The vast
-------
DRAFT
DO NOT QUOTE C.7 CITE
majority of evidence in this regard comes from observations among in-
dustrially exposed individuals. In reviewing these studies of non-
malignant effects among individuals exposed to vinyl chloride, several
criteria for evaluation were established. Included among these criteria
were the following:
-- Were control group comparisons made either with workers not
occupationally exposed to vinyl chloride or with members of the general
population? If control group comparisons were included, how closely were
these groups matched to exposed individuals?
-- Were important covariates considered among exposed and control
groups such as age, sex, race, alcohol intake, drug intake, exposure to
other toxic chemicals either in previous or present occuoations or in the
non-work environment, age at time of first exposure, latent period since
onset of exposure and duration of exposure?
-- Adequacy of physical examinations and laboratory tests. Were
physical exams performed? What laboratory tests were employed? Are
laboratory test specific for injury caused by vinyl chloride? Were bio-
chemical tests performed in the same laboratory and at the same period in
time? How adequate were quality control procedures in and among performing
laboratories? What were the cutoffs between normal and abnormal laboratory
findings? And were these consistent? Were duplicate tests run?
-- Adequacy of exposure estimations. Was exposure actually measured
or was it estimated? If exposure was estimated, how? If exposure was
based upon job categories, were factors such as age of the plant, and type of
plant (process and whether indoor or outdoor) considered?
V -24-
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DRAFT
DO NfiT QUOTF. OR CITE
It is recognized in establishing evaluation criteria such as listed
above that no single study could possibly consider every important factor.
This is particularly true with respect to many of the recent studies
which were performed in an effort to obtain as much possible information
in the shortest period of time. These criteria are useful
in examining conclusions drawn from existing studies and in identifying
gaps in knowledge that might appropriately be addressed in future studies.
All of the studies discussed in this regard are lacking in at least one
important area.
Evaluation of the acute effects from vinyl chloride were carried out
by Lester et. al in 1963, who reported on animal and human acute toxicity
22
experiments with VCM. Three men and three women were exposed for 5
minute periods twice each day, separated by a 6-hour interval, for three
successive days to vinyl chloride concentrations up to 20,000 ppm. Acute
toxic effects were observed at concentrations above 8000 ppm (dizziness,
nausea, dulling of visual and auditory cues, headaches, etc.). Follow-up
examinations of these subjects have not been performed to determine
whether or not such exposures produced any conceivable long-term, irreversible
effects.
23
Kramer and Mutcher correlated clinical and environmental measures
for workers exposed to vinyl chloride for periods up to 25 years. The study
population consisted of 98 healthy male workers. Exposure indices for these
men were based upon actual air measurements at Dow since 1950 and expressed
as cumulative dosage (ppm-years) and career time weighted averages con-
sidering the time each worker spent in critical job classifications. Ninety-
five parameters of history, physical examination and laboratory tests were
studied among exposed individuals and comparisons were made with workers
IX -25-
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DRAFT
DO NOT QUOTE OR CITIT
in other departments who had examinations during the same period of
time. Of 21 clinical parameters under study, 6 showed significant
correlations (P <0.05) with exposure variables, cumulative TWA and
cumulative dose. These significant parameters were systolic and
diastolic blood pressure, BSP retention, icterus index, hemoglobin
and beta-protein. The best correlation was between exposure and BSP
retention (coefficient of multiple determination, 0.4). Based upon
these observations the authors considered the possibility that "
repeated exposure to vinyl chloride at TWA levels of 300 ppm or above for
a working lifetime together with a very low level of vinylidene chloride
may result in slight changes in certain physiologic and clinical labora-
tory parameters. The possibility of some impairment in liver function
tests must be considered even though no overt clinical disease was
evident in any of the individuals studied."
It is noteworthy that a good dose-response relationship between
BSP retention and career TWA exposure was observed over the entire range
of exposure examined. Based upon the derived regression equation BSP
retentions of 12.5% were expected among those with TWA's of 300 ppm and
5.6% among those with TWA's of 100 ppm. A BSP rentention in excess of
5%,,is considered to be abnormal in clinical medicine and sug-
24
gests that substantial damage to liver cells may have occurred. Judging
from the data as presented, a small fraction of individuals with career
TWA's of 50 ppm had abnormal BSP retention tests
suggesting that liver damage had occurred. Exposure to other liver
toxins such as alcohol was not adequately considered in this study.
7,1-26-
-------
IJKAI- i
do sor q;joi£ os cite
Observations of liver damage, among workers who fabricate PVC plastic
into finished products as well as among workers who convert VC monomers
into the polymer indicate that injury to the liver among exposed workers
is important and that such damage may occur at lower levels of exposure
than is usually encountered in the production of PVC. In studies from
Germany, enlarged livers and spleens as well as abnormal tests of liver
function were found in PVC production workers.25'26 Liver histology
from specimens obtained during laparoscopy revealed evidence of liver
pathology in a high percentage of cases. These workers had a history
of employment ranging from 1^ to 21 years but no measures of past vinyl
wCehre011eThSUcoentrori g^ups'16 ^ U ^ ^ ^ Whether adequate c™P^sons
Following these initial reports of liver damage in PVC production
workers from Germany, additional studies were carried out in 50 individuals
with varying durations of exposure to vinyl chloride during the production
27
of PVC. These studies indicated that there was a relation between the
duration of exposure to vinyl chloride and the severity of liver damage
as determined by histologic examination of biopsy specimens. The most
severe evidence of liver pathology was observed for workers with an
exposure history in excess of 10 years.
Two cases of liver angiosarcoma were observed
among these 16 German workers with a history of exposure to vinyl chloride
*7.i-27-
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!.»iv i:,!' j
do r;jT !;!.::rr o? cite
of 10 years or more and all workers in this category exhibited evidence of
liver abnormality. Among workers with exposure durations of three years
and under, all were found to have some form of liver damage, though the
severity of damage was generally less than found in workers with greater
durations of exposure. Of note is that all 5 workers examined who were
not directly involved in the polymerization of vinyl chloride showed signs
of minimal damage to the liver parenchymal cells. These observations
coupled with reports of hepatomas in animals exposed to vinyl chloride
suggests that liver parenchymal cells may be damaged by vinyl chloride.17
Although these studies do indicate a relationship between exposure
duration and histologic evidence of liver damage, the lack of exposure
data on these workers makes it difficult to determine what levels of
exposure may have been responsible for such damage. Failure to compare
exposed workers with a suitable control group not exposed to vinyl chloride
and failure to consider the effect of alcohol intake are other limitations
which deserve mention.
Examinations of 70 out of 128 workers in a PVC production plant re-
vealed evidence of extensive abnormalities based on biochemical indicators
28
and other tests. These workers were employed an average of 7.7 years in
the industry (range 6 months to 21 3/4 years). Upper abdominal complaints
were present in 42 of 70 workers and symptoms such as tiredness, dizziness,
parasthesias and arthralgia were frequently reported. Thrombocytopenia,
increased BSP retention, and splenomegaly were present in a majority of cases,
81,67 and 57% respectively. Reticulocytosis was also common (41 •%) and
abnormal liver enzymes,esophaqeal varices and leucopenia were also observed.
Unfortunately, effects of exposure, both level and duration were not evaluated
in this study. Further, the frequency of abnormal findings among workers
7.1 -28-
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DRAFT
--0 i'iOT i'JUDjC CR riIE
not exposed to vinyl chloride was not studied so that it is difficult to
accurately judge the effects of such exposure. Findings such as splenomegaly,
thromborytopenia and increased BSP retention in the majority of instances
does, however, suggest that damage.in excess of the expected
frequency among the general population had occurred in these workers though these
changes were not necessarily specific for vinyl chloride.
To assess the possible implications of these findings, additional
studies were carried out among workers in Germany employed in PVC processing
plants. Such workers would have had a somewhat lower exposure than those
involved in the direct polymerization of PVC from the monomer though they
would be exposed to vinyl chloride as for example during rolling and shaping
operations particularly when heat was required. Medical examinations were
conducted among 15 such workers who were employed an average of 5 years,
29
ranging from \h to 13 years. Seven of these workers complained of
pressure and/or pain in the upper abdomen. Thrombocytopenia and increased
BSP retention (a test indicating abnormal functioning of the liver) were
found in 7 of 15 workers though not necessarily concommitantly. One
worker was observed to have an enlarged spleen. Of 4 workers in this group
who underwent laparoscopy and liver biopsy, one showed histologic evidence
of liver damage similar to, though less severe than, that observed
in PVC production workers.
Though comparable control groups were not examined, the similar histo-
logic damage in one worker to that found in PVC production workers suggests
that lower level exposures to vinyl chloride (unfortunately not measured)
may also cause liver damage.
7.1 -29-
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DRAFT
DO fiCT QUOTE DP, CIF
Some, but not all, investigations carried out in the United States
also observed liver damage among workers exposed to vinyl chloride. At
the B.F. Goodrich plant at Louisville, Kentucky, for example, 1183 em-
ployees had blood tests to screen for evidence of liver damage. These
workers included individuals involved in other than the direct production
of PVC such as maintenance personnel, administrators and secretaries. On
an initial screening test (SMA-12), 315 of 1183 or 26.6% showed at least
one abnormal blood test and 41 or 3.5% had 2 or more abnormal tests.
Among the 315 tested for a second time, 75 had a persistent abnormality.
The most common observed abnormality in this test was an elevated alkaline
phosphatase although increased bilirubins and SGOT's were also observed.
Based upon this initial battery of screening tests, 116 individuals
were given more extensive blood tests which indicated the presence of some
abnormalities in 59 or about 50% of those examined. Seven of these indi-
viduals had major abnormalities which required additional procedures.
The highest percentage of abnormal batteries (10.9%) occurred among PVC
production workers, although abnormal batteries were also found in other
production workers, in maintenance workers and in non-production workers
such as clerical personnel.
Depending upon results from the battery of tests, more elaborate
diagnostic procedures such as liver scans, hepatic arteriograms and liver
biopsies were initiated. Of 17 individuals undergoing such tests, 11 cases
of portal fibrosis, indicating severe damage to the liver were uncovered,
Two of these cases occurred amonq workers not directly involved in the Droductinn
of PVC raising the possibility of damaqe at relatively lnw levels of exposure.
In 2 of these 11 workers, both involved in PVC production,
7.i -30-
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I
p r1."' r nr , - -
L >j i >t > I j \ I i u;,
angiosarcoma of the liver was found.
While this study in Louisville did document
evidence of damage related to vinyl chloride; i.e. liver angiosarcoma,
it is not at all clear from this study, the extent to which less severe
liver damage may or may not be related to vinyl chloride. Although there
is suggestive evidence that less severe damage may also have occurred,
.adequate comparisons were not made with matched control groups,
and measi^rements of vinyl chloride exposure were not made. Accordingly,
le'vel of exposure could not be related to observed effects. Failure to
correlate abnormal tests with duration of exposure or with latent period
since onset of exposure, and lack of consideration of alcohol intake are
additional limitations in this study.
Studies carried out in a PVC production plant in
Niagara Falls did consider several of the factors not examined in Louisville;
i.e. duration of exposure and alcohol intake but unfortunatley did not measure
exposure directly. In this instance, a total of 354 workers were examined,
267 of whom were currently employed in a vinyl chloride polymerization plant
encompassing nearly the entire work force. Also examined were 87 former
workers. Hepatosplenomegaly was observed in a high percentage of current and former-
ly exposed worKers (15.0 and 3.4% respectively) with the most frequent
occurrence in each category among workers exposed for 20 or more years.
Though hepatosplenomegaly was generally less frequent among former workers,
in present workers hepatosplenomegaly was observed among 6% of workers with
a history of exposure not greater than 2 years' duration and there was a
7/ £ -31- LIBRARY /EPA
Natiorel Environmental Research Cents?"
200 S W 35th Street
Corvallis, Oregon 97330
-------
n.r>
fr
- i
I
Z or\
sharp increase in this abnormality among workers exposed for more than
5 years. Nearly one-third of current workers exposed for 20 or more years
showed enlarged livers or spleens. Though hepatosplenomogaly was generally
higher in each exposure category among those with a history of significant
alcohol intake compared to those with no significant intake, in each group,
the frequency of hepatosplenomegaly was related to duration of work ex-
posure. Abnormal tests of liver enzymes were also present even among those
with exposures of not more than 2 years' duration and these abnormalities
were generally more frequent with increasing duration of exposure. It is
of note that elevated alkaline phosphatase, the most frequently observed
biochemical abnormality, did not correlate well with ethanol intake but
did correlate significantly with duration of exposure to vinyl chloride.
In addition to finding evidence of liver involvement in these workers, ab-
normal tests of pulmonary function and abnormal chest X-rays were also
associated with increasing durations of exposure to vinyl chloride.
While the relation of abnormal findings with duration of exposure
suggests an effect related to vinyl chloride, failure to compare these
results with the frequency of abnormalities in a matched control group
not exposed to vinyl chloride is an important limitation. Without such
information it is difficult to evaluate the true significance of these
fi ndings.
As noted above, not all U.S. studies observed effects among workers
exposed to vinyl chloride. One such "negative" study involved an evaluation
of health surveillance data on 335 workers with industrial exposures to
7,2 -32-
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D0 r';- v-'CiE 0? C!
32
vinyl chloride at the Dow Chemical Company. This survey was based upon
a multiphase screening program that had been available to employees at
Dow since 1967. The study population was comprised of production employees
who had worked for at least one year between 1942 and January 1972 in areas
with potential vinyl chloride exposure who were also employees of the
Dow Midland Division between February 1967 and March 1974, the period of
the multiphasic health screening program.
Exposure categories were based upon industrial hygiene data that had
been compiled from 1950 and later using estimated time weighted average
concentrations for an 8-hour day. The high exposure group was defined as
those with exposures above 200 ppm for a duration of one month or longer;
the intermediate group had exposures from 25 to 200 ppm; and the low group
had exposures under 25 ppm. A fourth exposure category, undefined, was
established for those individuals for whom sufficient industrial hygiene
data was not available. A subjective evaluation indicated that most
individuals in this latter group were exposed in the low to intermediate
range. The participation rate in the multiphasic screening program was
about 80% in all exposure groups.
The availability of measured exposure data for most of these workers
provides a much more objective evaluation of past exposure levels than is
available from most other industrial studies. However, it should be noted
that by giving precedence to a period of one month's high exposure in
defining the highest exposure group, this category may have included
individuals with predominantly low level exposures throughout the majority
7, t -33-
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00 Ncr qijgic r„rE
of their work experience. On the other hand, the lowest exposure category
would not have included workers with a history of high level exposure to
vinyl chloride.
Because of revisions in the multiphasic screening program in 1970, the
data obtained before and after this date were analyzed separately. A
control group of matched pairs for sex, age, smoking history and month of
exam and where possible date of liire was included in the analysis. The
parameters studied prior to 1970 included tests of pulmonary function,
blood pressure, white blood count, total bilirubin, SGPT and alkaline
phosphatase. The only statistically significant difference (P <0.05)
between exposed and matched pair control groups was for decreased diastolic
blood pressure in the high exposure group. No differences between exposed
and control groups were noted in terms of pertinent historical questions
including shortness of breath, chronic cough, jaundice, gastrointestinal
trouble, numbness in hands or feet, cancer, anemia or blood problems.
The health surveys conducted from January, 1971, included similar
historical information and laboratory tests for pulmonary function, hemoglobi
white blood count, SGOT, LDH, total protein, protein albumin and protein
globulin. Statistical analysis of alkaline phosphatase was not performed
due to changes in laboratory procedures. No statistically significant
differences between exposed and control groups were found.
The availability of measured exposure data and the comparability of
laboratory results with the inclusion of matched pair controls for
each exposure category in this investigation overcomes many of the iniDortant
7,2 -34-
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np>irr
DJ NUT IJIJOiL (•.« CITE
shortcomings in other available studies. Labk of information as to possible
toxic chemical exposure in the matched pair controls and failure to consider
the impact of duration of exposure to vinyl chloride are, however, important
shortcomings in this study. 3y defining the study population as those who
had been exposed to vinyl chlordie for at least one year without further
considering the impact of duration of exposure, the exposed groups may
not have included a sufficient number of individuals with longer durations
of contact with vinyl chloride to necessarily be manifest in effects. A
major addition to this study would have been the inclusion of clinical
data based upon physical exams and additional laboratory studies both of
which, however, are planned for the future. Based upon the available date
the author concluded " below 200 ppm nothing of statistical significance
has been observed." It is, however, considered unlikely that the high
exposure group was really exposed to TWA exposures of 200 ppm over the lifetime of
their employment since high exposures of only one month's duration were
sufficient to plase an individual into this category. As noted above, an
earlier study at Dow suggested that liver damage may have occurred amono some
workers with TWA exposures of 50 ppm.23*
Kotin reported the results of a study of currently employed workers
exposed to vinyl chloride at Air Products and Chemicals, Inc. facilities
as well as the results of a death certificate survey of PVC employees who had
left the company or died while employed at the company. Plants at Calvert
City, Kentucky, and at Pace. Florida were included in this survey. A
detailed medical history was taken on each employee examined and physical
exams with X-Rays and laboratory procedures were performed including tests
of liver function.
7. I - 5
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DRAFT
00 NOT CUCIi r.R CITF
At Pace, Florida, 13 of 201 employees examined were found to have ab-
normal findings. Persistent minor abnormalities were found on retesting of
3 employees but these were not considered sufficient to justify further
immediate retesting although retesting 90 days later was scheduled. The
remaining 6 employees were given liver scans, all of which were normal. One
case of acroosteolysis was found at Pace, Florida.
At Calvert City, Kentucky, tests were performed on 291 employees, 97
of whom showed an abnormality on initial testing, partly due to equipment
malfunction. Following retest, 29 employees showed persistent abnormalities,
16 of which were considered equivocal, not justifying further immediate
additional testing but indicating retesting 90 days later. Among the 13
employees who were immediately retested, 6 showed findings indicating the
need for further laboratory and physical exams. Of these,2 cases of
Gilbert's disease, and 2 cases of gallbladder disease were found,
including one with coexistent hepatitis. An additional case of chronic
persistent hepatitis without gall bladder disease was found.
Examinations of the death certificates did not indicate any relation-
ship between exposure to vinyl chloride and cause of death.
the authorlhconclu5i|8tlialu1tS' 0XC8pt for the one case of ^osteolysis
/there was no evidence to identify vinyl chloride as a causative agent in
disease. No cases of angiosarcoma were identified in this survey.
In presenting these data no indications are given as to how age, level and
duration of exposure may have varied among these who were tested. No
definition of what constituted an abnormal test was given and no effort
7,1 .36-
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DO NOT Qi'OIL f.n ZWC
was made to contrast exposed workers to a comparable control group.
Measurements of vinyl chloride exposure were not made nor is there any
indication as to what percentage of workers examined were suspected to
have high vinyl chloride exposures. The adequacy of followup among workers
who had left the plants with respect to the death certificate survey is
similarly not indicated, and no data are presented as to the frequency of
abnormal findings on physical exams, particularly enlarged livers and
spleens. While it is encouraging to note that no cases of angiosarcoma
were observed, careful followup of these workers would appear indicated,
18
particularly since both plants under study were opened in the late 1950's-
Accordingly an adequate latent period following onset of first ex-
posure may not have been present to allow effects such as liver angiosar-
coma to be evident.
A survey of 36 PVC plants was conducted to determine if there were
factories in which no cases of liver angiosarcoma were observed despite
the presence of adequate exposure to vinyl chloride to have caused disease
20
as defined by time and concentration. Plants in which angiosarcoma had
occurred were not included in the analysis. Similarly plants with operating
experiences of 10 years or less were also discarded from the analysis.
The remaining 16 plants included 2,372 persons currently employed and 1,471
previously employed, not all of whom had durations of exposure long enough
to be manifest in angiosarcoma. Included among these individuals, however,
were 787 persons who had worked more than 10 years and 104 persons who
had worked more than 20 years with vinyl chloride. Also included were
7. 3 -37-
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nr-,r|
01' ,\J! ;;'uui L OR C'TE
1,402 persons with a time lapse since first vinyl chloride exposure uf more
than 10 years and 416 persons with a time lapse of 20 years or more.
Of these 16 plants only 2 had conducted measurements of vinyl chloride
concentrations prior to 1970. Accordingly, the presence of vinyl chloride
odors was used to estimate past exposures. The odor threshold for vinyl
chloride is in the vicinity of 250 ppm though it may be much higher. On this
basis 4 companies indicated that vinyl chloride odors were detectable for
most of the work day prior to 1960; only 2 of 16 plants reported odors
most of the day between 1960 and 1970 and no plants reported odors this
frequently after 1970. However, all 16 plants reported the occasional
presence of vinyl chloride odors at some time in the past although this
was never considered to be a rare event, particularly prior to 1960. In
view of these observations, exposure to time weighted average concentrations
of vinyl chloride were considered to have exceeded 50 ppm in recent years
and 250 ppm prior to 1960.
Since January 1, 1974, 3,285 examinations were conducted on employees
in these companies including 872 retirees. This constitutes a follow-up
rate of nearly 90% of all employees, but only 60% of those who were
previously employed. Of these men, 3,249 were given liver profile tests
as included in the SMA-12, i.e. bilirubin, SG0T, LDH and alkaline phosphatase.
An abnormality in one of these four tests was reported in 15% of those
examined, but this fell within the levels of abnormality observed among
900 Union Carbide employees not exposed to vinyl chloride and 400 office
personnal with no known occupational chemical exposure. Similarly, the
71 -38-
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occurrence of abnormalities in 2 tests (2.7%) and in 3 tests (1.3%) were
comparable to those found in control groups. No mention is made of reports
of findings on abnormal physical exams. In making these comparisons, no
information is given as to the makeup of vinyl chloride exposed compared to
control groups particularly with respect to covariates that may have
affected test results. Similarly no definition of an abnormal test is given
and there is no information as to quality control efforts among the various
laboratories participating in these tests.
Based upon these observations the author concluded that "Examinations
of these men have failed to show the existence of abnormal liver function
tests in greater proportion than would be found in a control popul«tion.
There is no case of angiosarcoma of the liver among these 1,402 men even
though their exposure time is sufficient for disease to have occurred...."
In drawing this conclusion, however, it should be noted that only 104
individuals had worked more than 20 years with vinyl chloride and 416
individuals had a time lapse since first exposure of 20 years or more.
This would seem important since, of the 19 worldwide reported cases of
angiosarcoma among PVC workers for which details are available, 15 had
a time lapse since first exposure of 15 years or more and 14 had 15
2
years or greater exposure to vinyl chloride.
7 1 -39-
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KT.
r
I
' o:;-
i.
Considering the lack of information on control and exposed
groups and the many laboratories participating in these analyses, it
appears difficult to draw any conclusions with regard to the frequency
of abnormal liver function tests among these vinyl chloride workers. The
fact that only 60% of former workers who may have had the greatest durations
of exposure were included in these examinations of liver function tests
is a serious shortcoming, as is failure to examine the influence of duration
of VC exposure upon abnormal liver function tests.
A summary of the data showing non-malignant effects of vinyl chloride is
shown in Table 7.3.5. results of these studies and their limitations
have been discussed above.
These observations of liver injury among PVC workers and particularly
among workers not directly involved in PVC production, have potentially
important implications with respect to the health of the general population
exposed to vinyl chloride. In reviewing these findings it is, however,
important to recognize that other toxic agents either work or non-work
related^uch as liver toxic drugs or alcohol could have contributed to
many of these abnormal findings. Further, some of the biochemical screening
tests are not specific for liver injury, though others such as BSP are.
Ideally, one would like to know the prevalence of liver injury among com-
parable non-industrially exposed populations before drawing final con-
clusions regarding the effect of exposure to vinyl chloride uoon the liver
from the above studies. Most studies were lacking in this regard. In
spite of difficulties with the present studies such as noted above, there
7- 3
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Table 7.3.5
SUMMARY OF OCCUPATIONAL FINDINGS RELATING
NON-MALIGNANT LIVER DAMAGE TO VINYL CHLORIDE EXPOSURE
Study Group
(Number studied)
PVC Production
workers 25 >26
PVC Production
45
workers
liver biopsy
study27
Post - PVC
polymeri zation
workers^ --
liver biopsy
study27
PVC Production
workers -- 7^,28
Level of
Exposure
Duration of
Exposure
Observed Effects
Unspecified
1*2 to 21 years
Unspecified a) 3 years and
under
b) 10 years and
more
Unspeci fied
Unspecified
PVC Processing
15 29
workers '
not involved in
PVC polymerization
but exposed to
PVC as a finished
product and hence
by inference exposed
to lower levels of
vinyl chloride
than PVC production
workers
Unspecified
Unspecified but
1ikely exposed to
lower levels of VC
than workers in-
volved in polymeria
zation process
Enlarged livers and
spleens
Abnormal BSP retention
Biopsy of liver showed
portal fibrosis
a) Biopsy showed mild liver
damage in all workers
b) Relation between duration
of exposure and severity
of damage with most severe
liver pathology observed
in workers with 10 or
more years of exposure
All 5 workers examined
showed evidence of mild
damage to liver
parenchyma based on
liver biopsy
6 mos to 21 3/4
years
(average 7.7 ye a rs)
to 13 years
Upper abdominal complai r,i
lethargy and pares-
thesias common complaints
Thrombrytopenia, increased
BSP retention and
splenemegaly found in
majority of workers
7/15 workers complained
of pressure or pain in
upper abdomen
Thrombrytopenia in 7/15
workers
Increased BSP retention
in 7/15 workers
Biopsy showed mild liver
damage similar to that in
PVC production workers
-------
Table 7.3.5 (Continued)
Study Group
(Number studies)
Level of
Exposure
Duration of
Exposure
Observed Effects
PVC Production
workers, and
non-PVC 20
production
workers (1183
total) 30
Unspecified Unspecified
Current and former Unspecified
PVC production
workers (354
total) 31
a) < 2 years a)
b) 5-10 years b)
c)
20 years
or more
c)
116/1183 or about 10%
ahowed significant bio-
chemical abnormalities;
abnormal liver function
tests found in non-PVC
production workers
11 cases of Dortal fibrosis
found on liver biopsy, 2
of which were in workers
not directly involved in
PVC production
Hepatasplonomegaly observed
in 67o of workers exposed
not more than 2 years
Sharp increase in
hepatasplonomegaly in
workers exposed greater
than 5 years
Nearly one-third of workers
exposed 20 years or more
had hepatosplenomegaly
Elevated alkaline phosphatase
correlated with duration of
exposure
Abnormal lung function
tests found
PVC Production
workers (98)^
PVC and non-
PVC production-,^
workers (335)
PVC workers
(492)33
TWA expo-
sures up
to 300
ppm
Up to 25 years
TWA
exposures
of 25-200+
ppm
Unspecified
1 year and
greater
Unspeci fi ed
Abnormal liver function
(BSP retention) correlated
with TWA exposures --
Evidence of abnormal BSP
retention at TWA exposures
of 300 ppm and suggestive
evidence of BSP retention
in some workers exposed to
TWA of 50 ppm
No adverse effects related
to angiosarcoma
One case of acro-osteolysis
only evidence of injury
attributable to VC
PVC workers
(3,843)20
Estimated as
greater
than 250
ppm prior
to 1960
Includes
exposed 20
years and
more
No increased abnormalities
above levels in control
groups
-------
DRAFT
r? NOT QIJCi I o," r,ITF
is suggestive evidence presented for at least minimal liver damage associated
wi th
vinyl chloride which may be observed with durations of exposure under
2 years. Though there is reason to believe that cessation of exposure to
vinyl chloride would cause a reversal in some of this damage; there is
also evidence that in some people, this damage is not fully reversible
and may even progress further. For example, one vinyl chloride production
worker examined by liver biopsy at the National Institute of Health showed
persistent and perhaps progressive liver pathology years after the
cessation of exposure despite an absence of abnormalities in biochemical
tests of hepatocellular function.^ There is also concern that the his-
tologic changes in the liver observed in PVC workers may represent pre-
trial ignant changes that would increase the risk of developing angiosarcoma
in future years.
Any final conclusions regarding the implications of these findings
for the general population who are exposed to levels of vinyl chloride
in the air generally much lower than in occupational situations must await
completion of additional studies. However, several observations do suggest
that exposure to vinyl chloride in the air may pose some risk to health at
these lower levels.
7 - '•
-------
DRAFT
7.3.1 REFERENCES DO MOT QIN.m'L C\~' rJTE
1. Heath, C.W., H. Falk arid J.L. Creech. Characteristics of Cases of
Angiosarcoma of the Liver among Vinyl Chloride Workers in the United
States. Paper presented at working group on Toxicity of Vinyl Chloride-
Poly vinyl Chloride. New York Academy of Sciences, New York City,
May 10-11 , 1974.
2. Wagoner, Joesph K. National Institute of Occupational Safety and Health
Statement Presented before the Subcommittee on the Environment Commerce
Committee, United States Senate, Washington, D.C., August 21, 1974.
3. Popper, Hans and Louis B. Thomas. Alterations of Liver and Spleen Among
Workers Exposed to Vinyl Chloride. Thomas, Louis 3. and Hans Popper.
Pathology of Angiosarcoma of the Liver Among Vinyl Chloride - Polyvinyl
Chloride Workers. Papers presented at Working Group on Toxicity of
Vinyl Chloride - Polyvinyl Chloride. New York Academy of Sciences,
New York City, May 10-11, 1974.
4. Epidemiology Notes and Reports, Angiosarcoma of the Liver - Connecticut.
Morbidity and Mortality, Center for Disease Control, V. 23, #29, June
15, 1974.
5. Letter of June 19, 1974 from Philip J. Landrigan. CDC to Nancy Beach,
EPA with accompanying memo of June 16, 1974, entitled Angiosarcoma of
Liver, Connecticut, from Medical Epidemiologist, Bureau of Smallpox
Eradication to Director, CDC.
-------
5. Letter from Louis B. Thomas, NCI to Philip Landrigan, CDC, dated
July 31 , 1974.
7. Memo for the Record: Report of an Angiosarcoma Case. Prepared by:
Dr. Robert Biggar, Country Health Department, Rochester, N.Y., April
9, 1974.
8. Letter from Henry Falk, CDC to Kenneth Bridbord, EPA, dated August 14,
1974 with enclosed autopsy report.
9. Maltoni, C. and G. Lefeimine. Carcinogenicity Bio-Assays of Vinyl
Chloride: Current Results. Paper presented at working group on Toxicity
of Vinyl Chloride-Polyvinyl Chloride. New York Academy of Sciences,
New York City, May 10-11, 1974.
10. Epidemiologic Study of Vinyl Chloride Workers. Prepared by Tabershaw/
Cooper Associates, Inc., Berkley, California, Final Report, submitted
to Manufacturing Chemists Association, Washington, D.C., May 3, 1974.
11. Tabershaw, Irving R. and William R. Gaffey. Mortality Study of Workers
in the Manufacture of Vinyl Chloride and its Polymers. J. of Occ. Med.,
16: pp 509-516, August, 1974.
12. Holder, Ben. The Dow Chemical Company Testimony Presented at Public
Hearing—Proposed Standard for Occupational Exposure to Vinyl Chloride.
U.S. Department of Labor, Washington, D.C. June 25, 1974.
13. Monson, Richard, R., John M. Peters, and Maurice Johnson. Mortality
Among Vinyl Chloride Workers. Paper presented at NIEHS Conference,
Pinehurst, N.C., July 29-31, 1974.
7 ? -
-------
I' I \ ' I
fin f'P t r •; " riir
L U hi/1 v1 (• 1 v
14. Monson, Richard R., John M. Peters and Maurice N. Johnson. Proportional
Mortality Among Vinyl Chloride Workers. Lancet, pp 397-398, August
17, 1974.
15. Nicholson, William J., £. Cuylor Hammond, Herbert Seidman and
Irving J. Selikoff. Mortality Experience of a Cohort of Vinyl Chloride
Polyvinyl Chloride Workers. Paper presented at Working Group on
Toxicity of Vinyl Chloride - Polyvinyl Chloride. New York Academy of
Sciences, New York City, May 10-11, 1974.
16. Keplinger, M.L. et. al. Experimental Studies with Vinyl Chloride.
Paper presented at Working Group on Toxicity of Vinyl Chloride -
Polyvinyl Chloride. New York Academy of Sciences, New York City,
May 10-11, 1974.
17. Maltoni, Cesare and Giuseppe Lefemine. Carcinogenicity Bio-assays of
Vinyl Chloride: I. Research Plan and Early Results. Env. Res. 7:
pp. 387-405 (1974).
18. Memo from Kenneth Baker, EPA, to Kenneth Bridbord, EPA, entitled
Employment Exposure to Vinyl Chlordie (VC), August 28, 1974.
19. Daniel, Roger L., Dow Chemical Company, Testimony Presented at Public
Hearing - Proposed Standard for Occupational Exposure to Vinyl Chloride,
U.S. Department of Labor, Washington, D.C., June 25, 1974.
20. Dernehl, Carl U. Associate Medical Director Union Carbide Corporation,
Testimony Presented at Public Hearing -- Proposed Standard for Occu-
pational Exposure to Vinyl Chloride, U.S. Department of Labor,
Washington, D.C., June 25, 1974. (check date)
7 3 -t>
-------
I.-; ,, I
VO foOT Q'JGI •: C."? CiTC
21. Wagoner, Joseph, NIOSH
22. Lester, 0., L.A. Greenberg, and W.R. Adams. Effects of Vinyl and
Repeated Exposures of Humans and Rats to Vinyl Chloride. Industrial
Hygiene Journal, May-June 1963.
23. Kramer, C.G. and J.E. Mutchler. The Correlation of Clinical and
Environmental Measurements for Workers Exposed to Vinyl Chloride.
Am. Ind. Hyg. ASsoc. Jour. 33: pp 19-30, 1971.
24. Harrison's Textbook of Medicine
25. Juhe, S., C.B. Lange, G. Stein and G. Veltman. Uber die sugenannte
Vichlchlorid - Krankheit. Dtsch. Med. Wschr. 98, pp 2034-2037, 1973.
26. Marsteller, H.J. Chronic Toxic Liver Damage in Workers Engaged in
PVC Production. Deutsche Medizinische Wochenschift. 98, 2311-2314,
1973.
27. Gedigk, P. Merphdogy of Liver Damage Among Polyvinyl Chloride Pro-
duction Workers: A Report of 51 Cases. Paper presented at Working
Group on Toxicity of Vinyl Chloride-Polyvinyl Chloride. New York
Academy of Sciences, New York City, May 10-11, 1974.
28. Veltman, G., C.E. Lange, S. Juhe and V. Bachner. Clinical Manifes-
tations and Cause of Vinyl Chloride Disease. Paper Presented at
Working Group on Toxicity of Vinyl Chloride-Polyvinyl Chloride. New
York Academy of Sciences. New York City, May 10-11, 1974.
7.3- ~ 7
-------
DRAFT
DO MOT Q:,0iL cn CITE
29. Lange, C.E., S. Juhe, G. Stein and G. Veltman. Further Results in
Polyvinyl Chloride Production Workers. Paper presented at Working
Group on Toxicity of. Jjnyl Chloride-Polyvinyl Chloride. New York Academy
of Sciences. New York City, May 10-11, 1974.
30. Creech, J.L. and L. Malck. Liver Disease Among Polyvinyl Chloride
Production Workers, paper presented at Working Group on Toxicity of
Vinyl Chloride-Polyvinyl Chloride. New York Academy of Sciences. New
York City, May 10-11, 1974.
31. Lilis, R. et. al . Prevalence of Disease Among Vinyl Chloride and
Polyvinyl Chloride Workers. Paper presented at Working Group on Toxicity
of Vinyl Chloride-Polyvinyl Chloride. New York Academy of Sciences.
New York City, May 10-11, 1974.
32. Cook, Ralph R., The Dow Chemical Comapny. Testimony presented at
Public Hearing -- Proposed Standard for Occupational Exposure to Vinyl
Chloride, U.S. Department of Labor, Washington, D.C., June 25, 1974.
33. Kotin, Paul, Consultant to Air Products and Chemicals, Inc. Testimony
Presented at Public Hearing - Proposed Standard for Occupational Exposure
to Vinyl Chloride, U S. Department of Labor, Washington, D.C., June 25,
1974.
34. Berk, Martin and Waggoner. Persistence of Vinyl Chloride Induced Liver
Injury after Cessation of Exposure. Paper presented at Working Group
on Toxicity of Vinyl Chloride-Polyvinyl Chloride. New York Academy of
Sciences. New York City, May 10-11, 1974.
~3 - ^
-------
7.4 Ecology
The potential problems associated with release of vinyl chloride into
the environment are just coming under scrutiny. For sometime it has
been known that the plastic, polyvinyl chloride is not biodegradable.
Microorganisms are not able to utilize the plastic or are able to do so
only after an extended period of weathering. Although acetylene and ethylene
1 2
are both capable of being reduced by microbial activity, ' their
chlorination seems to make them less amenable to attack
by microorganisms. Available evidence does indicated that alkenes may be
3
oxidized by heptone grown pseudomonas species. Very little is known
4
regarding the biological metabolism of alkynes.
The fact that polyvinyl chloride is not readily biodeqradable has led to
the difficulties attendant with the disposal of this form of plastic .
Incineration has been the chief means of disposal; however, this method
is not without its problems. Hydrogen chloride is generated in the
5
normal burning of refuse even when plastics are not present. During
burning, most of the chloride present in refuse and in the polyurethane
and polyvinyl chloride materials, which were added to the base refuse in
the test work, was evolved as hydrogen chloride. No free chlorine gas
or phosgene was detected. Though hydrogen chloride is evolved when burn-
ing refuse, the amounts released do not compare to those released when
polyvinyl chloride and polyvinylidene chloride plastics are incinerated.
Addition of polyethylene and polystyrene plastics to normal base refuse
containing no plastics had no effect on chloride ion emissions because
7
-------
rr A--*r ''' I
J Quote or qu^-
these plastics contain no chlorine. Addition of polyurethane foam
resulted in slight increases up to 689 parts per million (0.0689%) when
a 2% addition was made to the base refuse and 751 parts per million
(0.075%) when 4% was added. Adding polyvinyl chloride to the normal
refuse increased chloride 1on emission td 1990 parts per million
(0.1990%) for the 2% addition and to 3030 parts per million (0.3030%)
for the 4% addition.^
The effects of hydrogen chloride gas on vegetation have been known
since the mid-nineteenth century when damage was noted in the vicinity of
alkali plants in Europe and Great Britain. The concentration of hydrogen
chloride in stack gases was limited to 0.45 mg/m 1n 1874. No further
reports of crop damage due to this gas occurred after the passage of
the Alkali Act of 1906 in Great Britain. Damage due to hydrogen chloride
7 8 9
gas has been reported in the United States by Weiler, Hindawi and Wood.
Antipov reported hydrogen chloride gas damage to ornamental plants near
a chemical factory in the USSR which released fumes once or twice a month.
Species which were affected included oriental poppy, daisy, belleflower,
columbine, bluets, and pylox. The study by Wood is the only one which
specifically reported the combustion of polyvinyl chloride as the source of
the hydrogen chloride gas. The smoke from the combusion of polyvinyl
chloride insulation at a wire salvage operation in northern Pennsylvania
caused extensive damage to several northern hardwood species.
Bohne ^ reported hydrogen chloride gas damage to shrubs, trees and
flowers near a hospital incinerator.
7. 2^
-------
00-W Km CITE
Not all plants are sensitive to hydrogen chloride gas. Means and
Lacasse ^tested the sensitivity of 12 coniferous and broad-leaf tree
species to hydrogen chloride gas. The fumigations were conducted under
controlled conditions at a temperature of 27 C, relative humidity between
A O
78 and 85%, and a light Intensity of 1.4 x 10 ergs/cm sec. Under these
conditions the only symptom noted on conifer needles was a tip necrosis
on white pine at 8 ppm, on Douglas fir at 12 ppm, and on Norway spruce
at 19 ppm. Austrian pine and arborvitae were not injured at concentrations
of 18 and 43 ppm respectively. Symptoms on broadleaf species included
marginal and interveinal necrosis and necrotic flecking. Tulip poplar
was injured at 3 ppm, European black alder and black cherry were injured
at 6 ppm, and sugar maple and Norway maple were injured at 7 ppm. Red
oak was not injured at concentrations up to 13 ppm. These fumigations were
also of four hours duration.
The effects of hydrogen chloride gas on vegetation has not been studied
in any detail. This probably reflects its unimportance as a phytotoxicant.
Hydrogen chloride gas is easily scrubbed from flue gases and the major
sources are point sources; therefore, it has not been emitted into the
atmosphere in large amounts. The incineration of chlorine-containing
plastics in large amounts could change this picture.
Studies showing the effects of vinyl chloride in the environment
13
are extremely scarce. A study by Heck and Pires in 1962 indicates that
vinyl chloride can cause significant injury to plants. An analysis of the
results using five different fumigants at three different levels
7,*. 3
-------
c- N»rnn*n
WCTE CR CITE
ranked them in the following order, ethylene > acetylene > propylene >
ethylene oxide > vinyl chloride. Table 7.4'compares tne f1Ve compounds
and indicates the levels at which they were most toxic.
The injury symptoms shown for acetylene, propylene and vinyl chloride
were identical to that shown by ethylene. Ethylene is usually considered
as a physicologically active gas rather than a toxic gas, e.g. sulfur
dioxide. Ethylene affects a great number of physiological phenomena in
plants, such as ripening of fruits, abscission of plant parts, prolifera-
tion of tissue, inhibition of growth and variations in cellular metabolism. 14
Ethylene is a product of plant metabolism, but vinyl chloride has not been
reported from natural sources.
The effects of vinyl chloride upon microorganisms have not been
studied. As mentioned previously, there has been little work done
to determine whether alkynes can be metabolized by microorganisms.3
15
Ethylene is taken up by soil;- vinyl chloride may be also.
A by-product of vinyl chloride production, EDC-tar, has been disposed
of by dumping into the North Sea. EDC-tar is a mixture of short-chained
aliphatic hydrocarbons. When it is dumped into the ocean, it gradually
sinks toward the bottom. As the tar sinks, the components gradually
dissolve in the water. Therefore, its sedimentation rate is low. It
also has a tendency to adhere to a large variety of substances and form a
film or layer around the particles. Plankton are among those particles to
which the tar adheres.
Studies by Jernelov, Rosenberg and Jensen indicate that marine
animals rapidly accumulate EDC-tars from contaminated sea water. An
for
accumulation factor of 2900 was estimated/shrimp (Leander adspersus) exposed
to 0.01 ppm EDC-tar for 48 hours. The accumulation of low molecular weight
-------
DO
TaDle 7.4.) (omiwkison or the tonicity li.veu
OF IIIF. mill I. C tlNC I >"1 llATIO!\S Or FIVE FUMI-
CAM S ON ALL PLANT SPICCHS'
*1 o\lrltf
k»tlJ
Ftimigant
Conretilrallon
(ppm)
I
I fli)li nr o\l
-------
DRAFT
DO NOT QUOTE OR CITE
compounds of EDC-tar is highest via water, whereas the high molecular
compounds show the greatest accumulation through the food chain. These
i
conclusions are in agreement with the results of studies dealing with
Cl-C compounds such as DDT seawater. Dieldrin has also been shown to
accumulate rapidly through solution and much less slowly through the
16
food chain. When compared to DDT, PCB and other Cl-C aromatic
substances, the biological half-time is short (1 day to 3 weeks). This
fact may mean that the effects of ECD-components miqht not be as spvptp
as those of DDT, PCB's and other chlorinated hydrocarbons.
Studies made to determine the effects of EDC-tars on different
17
stages in the life cycle of the barnacle Balanus balanoides L. showed
that the stage II nauplii were ten times more sensitive than the
older stage V and VI larvae. Age, therefore, seems to make the
barnacles more tolerant to the EDC-tars.
In an attempt to determine some physiological aspects of EDC-tars
at the cellular level, the microorganism, Escherichia coli ijas
18
studied. The death of the intact cells was shown to be due to the
breakdown of the permeability of the cytoplasmic membrane. The authors
suggest that since most known biological membranes are formed according
to similar principles, the action of EDC-tar on the cell membranes of
higher organisms would be similar.
4
7./s2 Summary
Polyvinyl chloride plastics are not readily bioloqically deqradable. Thi
has led to incineration as a means of disposal.. Incineration of
polyvinyl chloride plastics results in the emission of hydrogen chloride
gas. Hydrogen chloride gas is injurious to plants, but emissions can be read
7-1/.
-------
DRAFT
DO NOT QUOTE OR CITE
controlled.
Vinyl chloride is damaging to plants. Injury to plants from
vinyl chloride is similar to that caused by ethylene; however, no
extensive studies have been made.
The effects of vinyl chloride on> microorganisms has not been
studied nor have the capability of microorganisms to metabolize it.
Ethylene is taken up by soil; vinyl chloride may be also.
EDC-tars, a mixture of short-chained aliphatic hydrocarbons,
are a by-product of vinyl chloride production. When dumped into
sea water, they show a tendency to be rapidly accumulated by marine
animals. The low molecular weight compounds have the greatest
accumulation.
In Escherichia coli the death of intact cells was shown to be
due to the breakdown of cytoplasmic membrane permeability. It is
suggested that because all biological membranes are formed according
to similar principles, the action of EDC-tar on the cell membranes of
higher organisms would be similar.
7 /
-------
7.f.i REFERENCES ^ QUOTE cr cite
1. Stanier, R.Y., M. Doudoroff and E.A. Adelberg. The Microbial World.
3rd. Prentice Hall, Englewood Cliffs, N.J. p873. 1970.
2. Zobell, Claude E. Assimilation of Hydrocarbons by Microorganisms.
Adv. in Enzymology X: 443-486. 1950.
3. Traxler, R.W. and W.L. Flannery. Mechanisms of Hydrocarbon
Degradation, in: Biodetorioration of Materials, Eds, A.H. Walters and
J.J. Elplver, Elsevier Pub. Co. Ltd., London, pp. 44-54.
4- McKenna, E.J. and R.E. Kelblo. The Biology of Hydrocarbons. Ann.
Rev. Microbial 19^183-208. 1965.
5- Kaiser, E.R. and Carotti, A.A. Minicipal Incineration of Refuse with
2% and 4% Additions of Four Plastics, A Report to the Society of the
Plastics Industry. New York, June 30, 1971.
6. Haselhoff, E., and G. Lindau. Chlorine and Hydrochloric Acid, pp.
230-256. Ijk Damage to Vegetation by Fumes. Handbook for the
Identification and Assessment of Fume Damage. 1903 (German).
7. Weiler, A. Corrosive Damage on Foliage Organs Caused by Acids and
Tarry Substances. Phytopath. 7/. 121-144. 1934.
8. Hindawi, I.J. Injury by Sulfur Dioxide, Hydrogen Fluoride, and Chlorine
as Observed and Reflected on Vegetation in the Field. J. Air Poll.
Contr. Asso. 18^:307-312. 1968.
9. Wood, F.A. The Influence of smoke from the Combination of Polyvinyl
V
Chloride Insulation on Northern Hardwood Forest Species. Phytopathology
58:1073. 1968.
10. Antipov, V.G. Resistance of Perrennials to Gases. Sadovodstvo
(Horticulture): 1:1-2 (Russian). 1956.
7-
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DRAFT
DO NOT Q1IC'T[ CR CITE
11. Bohne, H. Problems of Determining the Effect of Gaseous Chlorine
Emission Upon Plants. Staub-Reinholt. Luft 29:41-43. 1969.
12. Means, W.E.,Jr. and N.L. Lacasse. Relative Sensitivity of Twelve
Tree Species to Hydrogen Chloride Gas. Phytopathology 59^:402. 1969.
13. Heck, W.W. and E.G. Pires. Growth of Plants Fumigated with
Saturated and Unsaturated Hydrocarbon Gases and Their Derivatives.
The Agricultural and Mechanical College of Texas, Tezas. Agr.
Expt. Station. MP603. pl2. 1962.
14. Abeles, Frederick. Ethylene in Plant Biology. Academic Press.
1973.
15. Abeles, F. B., L. E. Croker, L. E. Forrence, and G. R. Leather.
Fate of Air Pollutants: Remove of Ethylene, Sulfur Dioxide, and
Nitrogen Dioxide by Soil. Science 173:914-916. 1971.
16. Jernelov, Arne, R. Rosenberg and S. Jensen. Biological Effects
and Physical Properties in the Marine Environment of Aliphatic
Chlorinated By-Products from Vinyl Chloride Production. Water
Research Pergamon Press. Vol. 6, pp. 1181-1191. 1972.
17. Rosenberg, Rutger. Effects of Chlorinated Aliphatic Hydrocarbons
on Larval and Juvenile Balanus balanpides L. Environ. Pollut.
3:313-318. 1972.
18. Hagstrom, A., S. Normark. Toxic Effects and Action of
Chlorinated By-Products from Vinyl Chloride Production on
Escherichia coli K12. Ambio. 3:77-79. 1974.
y.
-------
7.5 VINYL CHLORIDE IN PERSPECTIVE
The compejlinq evidence for the carcinoapnicitv nf vinvl chlnridp frnm
both an epidemiological and toxicological standpoint raises the question of the
possible carcinogenicity of other related chemicals in the ambient air. The
possibility exists of multiple exposure to a host of compounds that may
act additively or synergistically to produce a hazardous health effect.
Available data do not allow quantitative evaluation of the hazard of
multiple exposures. Published data, however, suggests that compounds similar
in metabolism to vinyl chloride which may appear of minor importance when
onlv low dosaapq nf inrtivirtual suhsta^ces are considered, could become
more important from a health standDoint when total "iulti-compound iosage is
evaldated.
J
7.^.1 Industrial Production and Use of Chemicals Related to Vinvl Chloride
and Polvvinvl Chioride
Structures, production figures and major uses for chemicals of
industrial importance with structure similar to vinyl chloride and polyvinyl
5
chloride are summarized in Table 7.^.1.
5
7.^.2 Carcinogenicity of Chemicals Related to Vinyl Chloride and Polyvinyl
Chloride
The publication "Survey of Compounds which have been tested for
Carcinogenic Activity"3 was used as the primary source of information on
the following chemicals:
1. 1,1-Dichloroethylene (vinylidine):
No data has hcen published.
2. 1,2-Dichlorn chylene:
No dat t has been published.
-------
Chemical
1,1-dichloroethylene
(Vinylldine Chloride)
Trichloroethylene
T etrachloroethylene
(Perch!oroethyl ene )
Vinyl Acetate
Polyvinyl Acetate
5
TABLE 7./.1
PRODUCTION AND USE IN THE UNITED STATES OF CHEMICALS
RELATED TO VINYL CHLORIDE AND POLYVINYL CHLORIDE
cl
\ /
? = c
cl H
cl cl
je = Q
Cl H
cl £1
Structure
H
cl
o
ii
cH3-c-o^
cl
c = c
s H
0
II
0 - c - CH.
L.CHo - CH . n
- I - n
Other Vinyl Polymers
(Alcohol, Butyral and Formal)
Production
(Million Pounds)
438(1972)1
745(1972)1
729(1969)2
422(1970)1
219(1970)1
Ma.ior Uses
Monomer for Vinyl Chloride Copoly-
mer and Polyvinylidine Chloride
Metal Degreasing, Manufacturing
Solvent
Dry Cleaning, Metal Degreasing.
Chemical Intermediate
Polymer Production
Textile Sizing, Adhesives, Paper
Coating, Polymerization Aid
-------
draft
3. Trichloroethylene4 NOT QUOTE OR CITE
Several animal species have been exposed to levels from 200 to 3000
ppm for up to six months with follow-up observations up to nine months. No
tumors were observed in any animals.
4. Tetrachloroethylene (Perchloroethylene)5
Various animal species were exposed for seven hours a day to 100-2500
ppm for up to 250 days with no tumors discovered.
5. Polyvinyl Chloride6
Film was implanted in various locations in rats for up to eighteen months.
Several tumors were observed, but all were in the area of the implant.
6. 1,1,2-Trichloropropene7
Rabbits were dosed orally with compound in oil at 0.1 LD50 for 6 months.
There was evidence of changes in lymph nodes after 18 months.
7. Vinyl Alcohol Polymer8
Implants of polymer sponges at various locations in rats for the life
span of the rats gave many sarcomas at the site of implantation and a few
tumors at other locations..
8. Vinyl Chloride Acetate Copolymer9
Implants in rats gave formation of tumors only at the site of
implantation.
For the most part, toxicological studies of chemicals related to vinyl
chloride have been limited to acute studies with only minor emphasis on long term
or carcinogenic effects. When carcinogenic studies were undertaken they were,
in qeneral, of insufficient exposure duration or involved too limited a
number of animals to provide conclusive negative results in this regard.
7
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DRAFT
DO NOT QUCTL' OR CITE
cf3
lL\ Other Carcinogens in Polluted Community Air
The array of contaminants identified in polluted community air in-
cludes other chemical and physical agents which are either proven or highly
suspect carcinogenic hazards such as polycyclic aromatic hydrocarbons,
azaheterocyclic hydrocarbons, certain metal compounds, asbestos and certain
radionuclides.. However, very few definitive studies have been con-
ducted to determine the contribution of these ambient pollutants to human
carcinogenesis. One of the observed epidemiologic characteristics of the world-
wide increase in lung cancer is the higher incidence in urban residents.
Although there are other factors which may contribute to urban and rural
differences such as population density and occupational differences, an
urban-rural difference in lung cancer rates persists even after correction for
these factors. Additional support for a probable etiological role for
ambient chemical carcinogens in lung cancer can be gained from several studies
12-14
undertaken to measure the effects of population migration on lunq cancer risk.
These studies in migrants have shown that either increases or decreases in lung
cancer are compatible with changes in environment. The chanaes in rates
parallel the general population concentrations in the areas under study and
persist after correction for cigarette smoking, although at a reduced level.
Moves from high pollution to low pollution regions reduced lung cancer death
5
rates and vice versa (Table 7.^.2). Within the United States and the United
Kingdom studies show a gradient of risk to lung cancer from low in rural to
high in urban areas. Migrants from rural to urban areas in the United States
appear to increase their lung cancer rates.
7
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Dr?AFT
^r1 T i.i rr > * -
is u i < v' I L •' L u • *
In a recent article,
Paul Koten draws attention to certain observations on the nature of car-
cinogens which should be considered when initiating studies of carcinogenesis
15
associated with air pollutants.
1. Cancer induction most frequently requires prolonged periods of
exposure to carcinogenic agents.
2. Cancer can be caused by several carcinogenic agents acting in
combination either in an additive, synergistic or inhibitory
relation to one another. This is particularly relevant to lung
cancer where a variety of ubiquitous environmental exposures to
carcinogenic agents exist.
3. The action of a carcinogenic agent in lung cancer induction may
be determined by the competency of the host's defenses at the
anatomic, physiological and biochemical levels. Polluted com-
munity air contains a large variety of chemical and physical
irritants, which though unable to cause cancer, facilitate the
action of carcinogenic agents by attenuating or destroying the
effectiveness of muco-ciliary apparatus of the lining of the lung.
This facilitates deposition and retention of particles carrying
carcinogenic agents. In addition, these irritants can induce
changes in the epithelium (metaplasia) which may enhance the
progression of changes to cancer. These irritants may alter the
metabolic handling of carcinogenic agents and thereby enhance their
cancer inducing potency.
4. There is evidence that at the cellular level, environmental chemical
co-factors of a highly non-specific nature may work together with
chemical carcinogens to increase their effectiveness.
7
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5
TABLE 7./. 2
AGE ADJUSTED DEATH RATES FROM LUNG CANCER IN
GREAT BRITAIN, NORWAY, AND THE UNITED STATES
Lung Cancer Death Rate
(Per 100,000 Persons)
Population Group Males Females
Great Britain residents 151.2 19.3
Great Britain born U. S. residents 93.7 11.5
Norway residents 30.5 5.6
Norway born U. S. residents 47.5 10.7
Native U. S. residents 72.2 9.8
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[iO flOT QUOTE 01? CITE
It would be wrong to consider vinyl chloride as an isolated situation,
but rather it should be viewed as an example of just one of many potential
chemical carcinogens which may be present but as yet unidentified as carcino-
gens. This suggests that more attention be given to the detection of other
chemical carcinogens in the myriad of industrial chemicals to which the general
population is exposed either as individual compounds or as multiple exposures.
;
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7.5J references 00 m WW OR CITE
1. Chemical Economics Handbook, Chemical Information Services, Stanford
Research Institute, Menlo Park, Calif., 1967 and additions.
2. Synthetic Organic Chemicals, United States Production and Sales, 1969
U. S. Tariff Commission Publication 412, Washington, D.C., U. S.
Government Printing Office, 1971, p. 206.
3. Hartwell, J. L., Survey of Compounds which have been Tested for Car-
cinogenic Activity, 2nd ed., U. S. Public Health Service, Bethesda, Md.
Publication Number (NIH) 73-35 or PHS149, Reprinted 1963.
4. Ib'id » Original publication, p. 44; Supplement I, pp 65-66; Supple-
ment II, p. 96; and 1961-1967 Volume, Section I, p. 351.
5. Ibid , Supplement I, p. 61.
6. Ibid , Supplement I, p. 67; Supplement II, p. 89; and 1961-1967
Volume, Section I, pp 199-200.
7. laid , 1968-1969 Volume, p. 98.
8. Ibid , Original Publication, p. 41; Supplement II, p. 88; 1961-1967
Volume Section I, pp 352-354.
9. Ibid . ! , 1961-1967 Volume, Section II, p 1851-1853.
10. Kotin, P., and H. L. Falk ''-F+ie Role and Action of Environmental Agents
in the Pathogenesis of Lung Cancer," Air Pollutants. Cancer ]_2: 147-163,
1959.
11. Kotin, P. and H. L. Falk. "Atmospheric Factors in Pathogenesis of Lung
Cancer," Advances in Cancer Research 7: 475-514 1963
12. Haenszel, W. Cancer Mortality among the Foreign-born in the U. S.
Journal of the National Cancer Institute 26: 37-132, 1961.
13. Haenszel, W., S. C. Marcus and G. G. Zimmerer. "Cancer Morbidity in
Urban and Rural Iowa. Public Health Monograph 37, Public Health Service
Publication 462, Washington, D.C. U. S. Government Printing Office,
1956 85 pp.
14. Reid, D. C., J. Cornfield, R. D. Markush, D. Seigel, E. Pedersen, and
W. Haenszel. Studies of Disease Among Migrants and Native Populations
in Great Britain, Norway and the United States. Ill Prevalence of
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Cardiorespiratory Symptoms among Migrants and Native-born in the U. S.
National Cancer Institute Monog. 19: 321-346, 1966.
Kotin, Paul. "Mutagenic and Carcinogenic Problems Associated with Air
Pollutants Proceedings of the Conference on Health Effects of Air
Pollutants. U. S. Govt. Printing Office Serial No. 9395 November 1973
pp 603-617.
•7. r
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8 CONTROL TECHNOLOGY AND REMEDIAL ACTIONS
8.1 INTRODUCTION
Most of the presently used or available technologies, are a ba^ic nart tho
processing system and serve to recover reactant or product. These controls
are appraised herein using performance data from the manufacturing plants,
or by comparing emission levels for plants with and without controls.
Controls so appraised for VCM production include:
recycling of vent streams, condensation with refrigeration, adsorption with
carbon, incineration, oxidation with ozone, absorption (scrubbing), and
venting to flares. Monomer loading and unloading involves special addi-
tional controls: vapor collection adapters with recycling, thermal level
detectors with recycling, and magnetic gages. Polymer production cjn
possibly benefit from consideration of controls indicated for the monomer
production, plus vacuum stripping, steam stripping, and the recycling of
carrier air streams.
A qualitative assessment of the potential applications of selected
controls has been made based upon information presented to date by U.S.
industrial firms. The results of this assessment are summarized for each
process in the following paragraphs. All percent reductions of emissions
are estimates.
8.2 MONOMER PRODUCTION
The relatively scarce data seem to point to a present total emission of
about 90 kg/mil lion kg of VCM produced. To this amount should be added a
smaller, intermittent loss of VCM in the loading area.
CI TF
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A 90 nercent reduction can be obtaineJ
by refrigeration
and/or absorption of vinyl
appropriate solvents (EDC for instance) and by
chloride in the vents by
combustion of the organics in other vent streams, followed by removal of HC1
produced. A 90 percent reduction is about at
the limit of present-day technology. For such a reduction the loading
area must be policed for vent losses.
8.2.1 VCM From Acetylene and HC1
The reactor vent is the main emissions source, accounting for 60 percent
of total emissions. Condensation at 44 UC (40 and 0.29 X lO^N/m0 (.35 I'sig) is now used
Addition of refrigeration would decrease emissions by about 50 percent. If an [if i scrubber
were also used, the combined controls should achieve 85 percent reduction.
These, combined with carbon adsorption, should reduce emissions 99 percent.
Recycling, incineration, oxidation with ozone, and venting to flares do
not appear to be applicable.
Fugitive emissions equal about 25 percent of total emissions. Use of
diaphragm valves, replacement of packed pump seals with pressurized mechan-
ical seals, use of vapor collectors on samplers, and preventive maintenance
can be expected to reduce these emissions by 50 to 95 percent.
Tank-car loading accounts for an estimated 15 percent of emissions
Incineration, with HC1 recovery should reduce condenser vent loses 99 percent.
Thermal level detectors combined with vent gas refrigeration and/or recycling would
reduce slip gage emissions by 95 percent. Replacing the slip gages with magnetlc
gages could reduce the emissions nearly 100 ofirccnt. Vapor collector adapters with
recycling would reduce purge losses 50 to 90 percent. Incineration should reduce
loading air emissions about 90 percent.
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8.2.2 VCM From Addition Reaction of Chlorine to Ethyi'efofe
iri Air Atmospheres Followed by Dehydrochlorination
Major emission sources are of VCM from the EDC light ends column vent
(9-20 percent) the heavy ends tar removal column vent (18 percent), the VCM
light ends column vent (10-13 percent), and tank car loading (10-20 percent).
EDC light ends column emissions could be reduced about 50 percent using
refrigerated condensers and nearly 100 percent with carbon adsorption. Re-
cycling to a post chlorination unit would be almost 100 percent effective.
Heavy ends column emissions are believed to be controllable by incinera-
tion (50 percent reduction), and by adsorption (close to 100 percent reduction)
VCM light ends would require adsorption or oxidation with ozone, both
capable of nearly 100 percent reduction.
Tank car loading controls given in Section 8.2.1 would apply here also.
8.2.3 VCM From Addition Reaction of Chlorine to Ethylene in Oxygen
Atmosphere should be Followed by Deliydrochlori'ifation
Major emission sources of VCM and their controls are believed to be
essentially the same as described in 8.2.2. The use of oxygen would reduce
the quantitative amounts of vent streams from the EDC product processing,
and thus would of itself reduce emissions somewhat.
8.2.4 VCM From Direct Chlorination and Dehydrochlorination of Ethylene
The controls are essentially the same as described in Section 8.2.2 and
would have about the same range of efficiency. This process must avoid IIC1
emissions by recovering it for other usage. Incineration with IIC1-recovery
by scrubbing is about 90 percent efficient for this purpose.
8.3 POLYMER PRODUCTION
In the production of polyvinylchloride, present monomer losses in kg/kg
of product are at least an order of magnitude higher than in the production
of VCM. Most producers report about a 3 to 4 percent lower PVC production
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than monomer intake. From some data submitted by manufacturers, 1 to 1.5
percent of PVC made is lost. A portion of this is emitted as fine parti-
culated to the atmosphere. The actual monomer emission is
therefore in the order of 2 to 3 percent. These losses result from the
batch nature of the polymerization operation and in the filtration and in the
drying t'ie polymer, xf practiced. Reduction of these losses poses a more difficult
if not an impossible problem. To indicate the severity of the problem, a
direct reduction to 50 percent of the present level of losses seems possible, but a
90 percent reduction of the emissions in some of the existing polymer plants without
process changes might be beyond present techniques at acceptable costs. However,
if intensive stripping of the suspension at the end of the reaction is allowable,
the 90 percent reduction might be feasible at acceptable costs.
One development should be noted, namely the move to progressively bigger
reaction vessels. One company has studied and is proposing use of a 45.4 m^
(120,000 gal.) polymerization reactor compared to the present typical size
3
reactor of 19 to 38 m (3,000 to 10,000 gal.) A possible emergency blowing of
emissions
such a reactor might, however, lead to very high peak values of vinyl chloride
This report has not considered the influence of VCM remain-
ing in the polymer. This residual monomer, sometimes present to about 1000 ppm, is
mostly released during further processing and might thus create emission pro-
blems during tabr" cation . rocessos/ -irticuij l'- tno^e involv;nc; heat.
8.3.1. Suspension Polymerization
Fugitive - emissions throughout the process account for an estimated 45
percent of VCM emissions. The emission sources must be better defined
before specific controls can be discussed. However, a good maintenance
program and minor equipment modifications should reduce fugitive emissions
by about 50 percent.
£
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DC HOT OUCTE OR Cr,t
Vacuum stripping of the crude product would be 50-80 percent
efficient for reducing emissions from the blend tank which accounts for
about 11 percent of the total emissions. Carbon adsorption would reduce this
source 50 to 99 percent; condensation with refrigeration, 50 to 70 percent:
incineration, 50 to 99 percent; absorption, 50 to 80 percent.
Collectively, vents from the dryer, the air conveyor, the storage
site, and wash water provide 35 percent of the total emissions. Vacuum
stripping and absorption are expected to give 50 to 80 percent reduction *ncl recycle- to
compressors, 40 to 60 percent reduction in emissions from these sources.
8.3.2 F.mulsion Polymerization
The dryer vent, air conveyor vent, site storage vent, and waste water
vent appear to account collectively for about 85 percent of total emissions.
Carbon adsorption, oxidation with ozone, and steam stripping could reduce these
emissions by 50 to 99 percent. The recycle of air streams could oc 4u to »u percent
efficient. Fugitive losses contribute 7 percent of the emissions; blend
surge tank vents contribute another 7 percent. Vacuum stripping, if
practiced would effect 50 to 80 reduction; carbon adsorption, 50 to 99 percent.
Condensation with refrigeration would reduce either source about 40 to 60 percent.
Absorption is expected to reduce both losses 50 to 80 percent. Preventive
maintenance would reduce fugitive losses 25 to 50 percent. The surge tank vents
could be recycled giving 40 to 60 percent reduction, or they could be oxidized with
ozone to provide 50 to 99 percent reduction.
8.3.3 Bulk Polymerization
The VCM reactor vent (25 percent) fugitive emissions (35 percent), and the
combined resin receiver, collector, and storage (20 percent) are the major
emission sources. For the reactor vent, adsorption (50 to 90 percent reduction),
oxidation with ozone (90 percent reduction), and incineration (50 to 90 percent
reduction) are indicated for control purposes. Intensive maintenance is believed to be
capable of -p/in:
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50 to 75 percent reduction of the diverse and ill-defined fugative emissions which
need further study. The product collection systems vents could be water-
washed, then adsorbed (50 to 90 percent reduction), oxidized with ozone (90 percent
reduction), or incinerated (50 to 90 percent reduction).
8.3.4 Solution Polymerization
While no data are at present available for this process, it is expected
to have the emission characteristics of the suspension process (section 8.3.1)
and to respond roughly to the same controls.
8.4 RESEARCH AND DEVELOPMENT UNDERWAV
Allied Chemical is developing
a technique for controlling hydrocarbon emissions from the oxychlorination
process. Control of vinyl chloride is expected to be a side benefit of
this work.
Industrial R&D groups are investigating the use of carbon sorption and
solvent scrubbing as gas stream cleaning techniques. They are also trying
to develop a more porous polymer form which will facilitate stripping of the
monomer from the polymer.
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REFERENCES
DRAFT
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Vinyl Chloride -- Assessment of Emission Control Techniques and Costs.
Internal EPA Report, July 1974.
t 7
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APPENDIX A
ESTIMATES OF RISK FROM LOW LEVEL EXPOSURE TO CARCINOGENIC CHEMICALS
Several statistical models have been developed for extending
observed response associated with several exposure levels (dose-response
curves) determined in experimental animals to undetermined response
dosages below those used experimentally and extrapolating these
theoretical considerations to estimate risk to human health with
regard to low level exposures to carcinogenic agents.
The estimated risk associated with exposure to vinyl chloride based
upon animal experiments has been presented using several of these
models and the available toxicologic dose-response dataJ
Mathematical Models
Models available for estimating risk associated with exposure to
carcinogenic agents fall into two main categories, i.e.those that deal
with tumor incidence as a function of dose and those that deal with
latent period modification as a function of dose (exposure level).
Several models designed to predict response beyond the limits of
available experimental data have recently been reviewed.
Strategies for assessing risk range from those that place emphasis on
safptv factors and hPS^ Fciopt-i^'c ji!dnQmert to those that involve
.... 4-7
statistical extensions beyond the limits of observed response data.
Among the important factors to be considered in the use of these
models are the following:
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00 NCT QUOTE OR CITE
Any exposure to a carcinogen may be associated with a certain
degree of risk. This risk is expressed with regard to a
particular carcinogen. However, multiple exposures to several
carcinogens and non-carcinogenic synergistic agents in general
are not considered in these models.
None of the available models have been adequately confirmed
by direct experimental studies at the very low end of the
dose-response relationship. Since these models represent
extrapolations beyond the limits of available scientific
data, they should not be construed as "scientific dogma."
Linear models of a quantal biological response (al1-or-none)
are useful for selection of a mean effective dose. In
estimating risk to the population, the slope of the extra-
polation curve and the confidence level selected for
estimating risk are extremely important parameters. The
intrinsic reliability of these models depends upon proper
experimental design with appropriate attention given to
biologic factors that may modulate response. It is extremely
important to note that linear models assume a no-threshold
effect level, and the level of risk determined by the slope
of the dose-response curve can be influenced greatly by the
experimental design and the selection of the model used.
A -2-
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f ¦' ' r ' r
i' >»¦ i r
do ,\)o; r
I s ,1' f
^ 1k v-i t a
These models are as valid as the assumptions made in
their design; e.g. it is assumed that the distribution
of sensitive, cancer prone individuals in the population
is represented by a normal (Gaussian) distribution.
A committee of scientists under the direction of the National
Academy of Sciences, Advisory Center for Toxicology have recently
reviewed biological and statistical considerations in assessment of
risk. This review soon to be published (January, 1975) is presented
g
here for those who desire a more in-depth discussion of these matters.
- 3
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! 24
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CHAPTER V lL ,.wj Civ CITE
SOME BIOLOGICAL AND STATISTICAL CONSIDERATIONS
IN THE ASSESSMENT OF RISK
CONTENTS
Page,
A. THE ROLE OF THE TOXICOLOGIST IN THE ASSESSMENT OF RISK 125
B. BIOLOGICAL CONSIDERATIONS 126
C. STATISTICAL CONSIDERATIONS 129
1 2Q
1. Expcriracntal Error and Sampling Error
2. Estimating Low Effect Levels
D. SUMHARY 133
LITERATURE CITED 135
f" ''i f 1 ' | -.¦»»!»
fiw.l V .... ..il t.,i' v. J./
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v. sour: biological and statistical considerations
IN THE ASSESSMENT OF RISK
Applying the results of toxicological investigations conducted in
the laboratory to the population of interest generally involves two kinds
of extrapolations. The first, which is more difficult to deal with and more
important with respect to human exposure, involves predicting the probable
effects on one species from the results of experiments performed on another.
The second kind of extrapolation is that of extending dose—response curves
beyond the limited range of observation to determine the dose corresponding
to an extremely low incidence of adverse effects on the organism tested.
A. THE ROLE OF THE TOXICOLOGIST IN THE ASSESSMENT OF RISK
objective technical information needed to make decisions on the course of
action to be followed to insure the safe use of chemicals. It does not, except
for a general statement of principles, go into the socio-political aspects of
decision-making.
Terms such as "toxicological insignificance," "safe," "zero tolerance,"
"no effect level," and negligible risk" have been In rather common use. All
of these contain in one way or another value judgments or technical Impli-
cations which have no place in an objective assessment of risk. There Is
no substance which, under certain circumstances,cannot be dangerous and unsafe.
There is no battery of tests, however elaborate, which can prove beyond chal-
lenge the complete safety of a chemical. For the toxicologist to apply the
terms "toxicologically insignificant" or "negligible risk" to a set of obser-
vations makes a premature judgment in the wrong arena by the wrong person as
to insignificonce or acceptability. An attempt has been made to eliminate such
terms from this report. A
This report concerns itself primarily with the task of developing
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Another common term of wide usage is the "no effect level." This
is statistically meaningless and therefore of limited value since it merely
means that no effect was observed in studies using a group of animals of
particular size. Such an observation is completely compatible with the pre-
sence of an adverse effect, which in further studies with larger sample sizes
or with different types of observation might lead to a positive outcome. We
prefer the usage of the term "no observed effect," which should always carry
with it a qualifying statement as to size of the group in which no adverse
effect was observed.
In most instances it will be imperative to develop a dose—response
relationship, and because many toxicological techniques are relatively insen-
sitive, high doses (which produce high incidence of effects) are frequently
required. These can be and have been called "unrealistic" or "inappropriate."
Such exposures may be well above, sometimes many orders of magnitude above,
likely levels of exposures to human or wildlife systems. Nevertheless, they
are often an essential part of practicable laboratory studies which necessarily
use limited numbers of animals. The underlying challenge to the toxicologist
is to use these points on the dose—response curve as a means of quantifying
responses, and to devise, with suitable margins of safety, appropriate means
for extrapolating to realistic, actual exposure conditions. The biological
aspects of this extrapolation will be discussed first, and the statistical
considerations wil] be developed later.
D. BIOLOGICAL CONSIDERATIONS
For clarity in the following, it will be assumed that we are con-
cerned with extrapolation from the laboratory situation to human populations.
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Except in the case of lifesaving drugs, only very low risks will normally be
accepted in chemical usage. The acceptable risk will, however, vary with the
benefit anticipated. In the case of risk of death from a chemical of trivial
utility, the acceptable risk would be essentially zero. Put in exploit terms,
this might mean 1 death in 100 million persons. As noted in the section on
statistics below, extrapolation to such risk levels from experiments on small
numbers of animals is extremely uncertain. Again, and as noted repeatedly in
this report, the gravity of the effect is a major determinant in an overall
assessment of risk. At one extreme lies a fatal outcome, and at the other, a
temporary functional alteration producing no disability or discomfort and lying
fully within the range of physiological compensation. The susceptibility of
human populations varies widely since genetic background, age, prior or co-
existent disease are all important determinants, and part of the toxicologist'a
task is to identify susceptible groups in the population as the basis for estab-
lishing limits of exposure.
Another and vital factor constantly facing the toxicologist is the
often striking biological differences between the effects of chemicals on labora-
tory species and on man. It has been repeatedly shown that no one species
(including non-human primates) has responses parallel to the human over a wide
range of the effects of chemicals. The choice of species must then be based on
a determination of the biological similarity in the responses to the chemical
under study.
In extrapolating from animals to man the transfer is often made on a
dose^per unit weight (milligram per kilogram) basis. This practice overlooks
the well demonstrated (Freireich et al., 1966) observation that dose per unit
surface area (mg/m2) is generally a better transfer parameter.
A-n
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1 W0J£ OR CITE '
There has been much loose talk about "thresholds." The term threshold
means "the entrance or beginning point of something." This implies (and is
normally so used) a discontinuity in the slope of the dose-response curve. True
discontinuities in biological phenomena are rare. However, they do occur. One
example is the threshold for glucose excretion by the kidney. Most biological
dose-response relationships appear to be smooth functions and in absence of con-
crete evidence dose—response curves should probably be assumed to be smooth.
Many dose-response curves have an "S" shape with a much lower slope at the low end
of the curve than in the mid-range. This could be regarded as a "quasi" thres-
hold. The steepness of the dose-response curve is an important consideration
for predictive purposes. A steep dose-response curve implies a sharp cutoff
(again, a "quasi" threshold) with decreasing dosage.
Some dose-response curves appear to be linear, especially when atten-
tion is limited to relatively low incidence rates. One example of thi6 is
cigarette smoking and lung cancer (Doll, 1967); there are many experimental
situation where this appears to be the case.
Despite the above comments, there are some biological
reasons for anticipating that with some chemical agents there may be something
approximating a true threshold. The biological basis for this is twofold:
(1) the possibility of a relatively greater effectiveness of repair mechanisms
at low dose levels; and (2) the possible presence of competing biochemical
processes which could convert the chemical to harmless products at low dose
levels. It is difficult to generalize on these mechanisms since they can be
expected to depend on the chemical and the species. Unfortunately, investiga-
tion of these questions has rarely been undertaken.
A-?
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123
In the past, these complex considerations have been clealt with prag-
matically by the use of arbitrary "safety factors."
C. STATISTICAL CONSIDERATIONS
The need for a proper consideration of statistics in the design of
toxicological experiments and in the interpretation of the results cannot be
overemphasized. First, before meaningful results can be obtained, attention
must be given to identifying and reckoning with possible sources of error.
Second, statistical techniques are available which can give meaningful esti-
mates of the level of exposure to chemicals corresponding to the level of risk
which the decision-maker considers acceptable.
1. Experimental Error and Sampling Error
The outcome of an experiment is normally dependent upon innumerable
factors, only 6ome of which are known and even fewer of which are controllable.
In dose-response experiments with animals, for example, some identifiable
factors influencing the outcome include (1) the composition of the particular
batch of test preparation, which typically represents a significant source of
variation in independent repetitions of the experiment, (2) animal variability,
(3) technician reliability, and (4) the precision of laboratory techniques
such as dilution techniques or dose preparation. Since such factors influence
the dose-response relationship, they represent sources of experimental error;
and hence independent replications which randomly sample the levels of these
factors are necessary in order
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to estimate their contributions in the measure of experimental error. If
major sources of variations are not considered in such replication, then sta-
tistical precision as reflected in the width of confidence intervals, for
example, may be grossly misleading.
When several major sources of experimental error can be identified,
a conceptually simple experimental design would consist of independent repli-
cates at each target dose level randomly sampled with respect to all sources
of variation. If batches from the chemical manufacturer represent a source
of variation, for example, then this design might assign each animal at each
dose level to a different batch of chemical from the manufacturer. If dilution
errors are non-negligible, then dilutions to target dose should be independent,
not only among dose levels but also among animals within dose levels. When
several such sources of errors exist, this conceptually simple, completely
randomized experimental design clearly becomes impracticable, and blocking
becomes a more feasible means of conducting the experiment. Thus, each batch
of the chemical from the manufacturer might be administered to a group of
animals at every test dose to produce, in effect, a separate dose—response
curve for each batch. For any one batch, the proportion of animals responding
at a given test dose is subject to sampling error due to such factors as animal
differences and possible errors in dilution which would result in each animal
receiving a slightly different test dose. At any given dose level, the pro-
portion responding also varies among batches; thus, the average proportion
responding at a dose level is subject to both sources of error, namely, the
sampling error within batches and the variability among batches, which together
comprise experimental error. A valid statistical analysis should utilize the
appropriate experimental error and not merely its sampling error component.
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Since standard statistical methods of bioassay often are addressed only to the
analysis of sampling error, there is need for caution in applying these methods.
2. Estimating Low Effect Levels
Estimation of low effect levels poses a difficult prob]cm. Direct
experimental estimation of the level affecting one percent of the population
may require several hundred animals to obtain adequate statistical precision.
For many reasons, particularly in human populations, much lower risks than
one percent are desired. A true no-effect level cannot be observed experimentally,
Any observed level has meaning only for a particular sample size.
The observation of no-effect for a group of animals may arise from
one of two reasons: (1) the dosage level may indeed be below the theoretical
no-effect level; or (2) the number of animals tested may have been inadequate
to give a high enough probability of detecting a biologically important change.
For example, a test on 20 animals may show no deleterious effect, but a test
on 100 animals, tested under the same conditions, may show one or more animals
exhibiting deleterious effects. Similarly, for a graded response, a small
sample may fail to provide enough statistical precision to detect a change
from baseline, whereas a larger sample may. Thus, an observed "no effect level"
has no absolute meaning since it depends on sample size and poorly estimates
the theoretical 'no-effect level" ;a better term would be the "no observed
effect level."
However, data from experiments in which no effects are observed are
useful in placing limits on the probable incidence of effects. For example,
if no animals out of 100 animals displayed a deleterious effect, it can be stated
with 99% confidence that fewer than t\.5% of animals tested under these conditions
-------
DRAFT
K NOT C'iCTE OR CITE 1:1
would exhibit deleterious effects. If tins level of ri.sk ls Loo high, more
animals can be tested. For example, observance of zero rfiumdls aifected out
of 1000 tested results in an upper 997,, confidence limit of only 0.46°L. To
reach an extremly low acceptable risk level in this manner generally requires
a prohibitively large number of animals.
The past practice of selecting some arbitrary fraction ol" "no effect
level" as a limit for exposure leaves one with no estimate of risk. However,
I
a fairly conservative estimate of the risk can be made by employing the
one-hit (one-particle) theory (Food and Drug Administration Advisory Committee
on Protocols for Safety Evaluation, 1971). This theory states that for low
dosages, if an experimental dosage is divided by a factor f, then its upper
confidence level of the risk is also divided by the factor f Such an approach
will often result in near-zero dosages for extremly small acceptable risks.
For example, if zero deleterious responses were observed in 450 animals
at a dose d, it can be stated with 997L confidence that the true response
rate is less than 17<> (one out of 100). The predicted dose for risk of
-4
one out of 1,000,000 would then be 10 d
An alternate means of estimating low risk exposure levels involves
extrapolation from parametric dose-response curves. Many different empirical
mathematical models may be fitted to a set of experimental data (Finney, 1964 ).
The probit and logistic curves have been commonly used in biology, for example,
and both curves may fit equally well in the region of experimental observations
(2% to 98% response range) but give widely different estimates for extapolated
responses. For example, the probit curve will predict a dosage level
approximately 140 times higher than the logistic curve for extrapolation
to a dosage expected to elicit one response in 1,000,000 animals. In some instances
M I I
-------
DRAFT iri.
DO MOT QUOTE OR CITE
(Doll, 1967) linear dose-response curves have been reported; often, however,
these cover only a relatively limited response range.
There 1s no assurance that the dose-response curve observed in the
experimental range of dosages will apply at extremely low response levels.
Mantel and Bryan (1961) suggest the use of a presumably conservative slope
of one probit for each factor of 10 in dosage level for extrapolating to low
levels of carcinogenic risk.
A more recent approach to the extrapolation of laboratory findings to
the establishment of standards or limits for human populations (Albert and
Altshuler, 197 3) has taken into account age at the time of the appearance of
the adverse effects as well as the frequency of its occurrence. In the case of
cancer from external sources, for example, it has been shown, both experimentally
and in humans, that with lower doses cancer appears later, that is, at increasing
ages. Under this concept, and assuming the availability of reliable data, it
should be possible to establish limits which would place the earliest occurrence
of malignancy at an advanced age, e.g., no more than 10% incremental likelihood
of cancer at age 95.
D. SUMMARY
In the past, toxicologists have not only made the laboratory assessments
of toxicity, but in many instances they have made the final Judgment as to the social
course to be taken on the basis of a particular.set of findings. Instead,
the technical experts should be charged with securing an objective independent
determination of the extent, nature, and frequency of adverse effects. They
should be asked to explain the relative gravity of these effects for the target
L, A;
-------
DRAFT
ro r.rj -n rr-pr
• I i. \ «./ 1 v v;> I L
system, be it humans or wildlife# Similarly, other Qualified technical experts
should be requested to make an objective assessment of the benefits of use and
of alternative materials or processes. However, the final judgment as to a
trade-off between an adverse health effect and a desired benefit is a social
decision and should be made with the participation of those who are affected.
This is not to say that technical experts using their technical expertise will
not participate, but it does state that they should not be the sole judges of
determining the balance between the benefit and the risk.
The dose-response curve is a valuable tool for assessing the safetv of
a chemical compound. Estimates of low effect levels are part of the information
leading to the ultimate designation of safe and acceptable levels. The statis-
tical problems of extrapolation from experimental dose levels to very low levels
and the estimation of appropriate errors are particularly troublesome but can
be handled if care is taken in the design and analysis of the experiments and
the interpretation of results.
Without supporting experimental evidence, however, statistical analysis
will never be capable of making the critical extrapolation from laboratory animals
to man.
-------
DRAFT
n0 f;c.T gu0TE 0R C(TE
Albert, R.E., and B. Altshuler. 1973. Considerations Relating to the
Formulation of Limits for Unavoidable Population Exposures to Environ
mental Carcinogens. pp. 233-253. In C.L. Sanders, R.H. Busch, J.E.
Ballou, and D.D. Mahlum, Eds. Radionuclide Careinogenesis. Proc. 12
Ann. Hanford Biology Symp. AEC Symp. Ser. #29 CONF-720505. National
Technical Information Service, Springfield, Va.
Doll, R. 1967. Prevention of Cancer: Pointers from Epidemiology.
Nuffield Provincial Hospitals Trust, London, 144 p.
Finney, D.J. 1964. Statistical Method in Biological Assay. 2nd Ed
Hafner Pub. Co., New York, 668 p.
Food and Drug Administration Advisory Committee on Protocols for
Safety Evaluation. 1971. Panel on Carcinogenesis report on cancer
testing in the safety evaluation of food additives and pesticides
Toxicol. Appl. Pharmacol. 20:419-438.
Freireich, E.J., E.A. Gehan, D.P. Rail, L.H.
1966. Quantitative comparison of toxicity
mouse, rat, hamster, dog, monkey, and man.
50:219-244.
Mantel, N., and W.R. Bryan. 1961. "Safety"
agents. J. Nat. Cancer Inst. 27:455-470.
Schmidt, and H.E. Skipper,
of anticancer agents in
Cancer Chemotherap. Rep.
testing of carcinogenic
i
-------
REFERENCES
1. Schneiderman, M.A. Mouse to Man-Extrapolation of Laboratory
Results to Human Disease. Presented to: The Working Group on
The Toxicity of Vinyl Chloride - Polyvinyl Chloride. The New York
Academy of Sciences, New York, New York., May, 1974.
2. Weil, C. S. Statistics vs. Safety Factors and Scientific Judgement
in Evaluation of Safety for Man. Tox. Appl . Pharm. 21:454-463,
1972.
3. Weil, C.S., Guidelines for Experiments to Predict the Degree of
Safety of a Material for Man. Tox. Appl. Pharm. 21^:194-199, 1972.
4. Food and Drug Administration Advisory Committee on Protocols for
Safety Evaluation; Panel on Carcinogenesis Report On Cancer Testing
in the Safety Evaluation of Food Additives and Pesticides. Tox.
and Appl. Pharm. 20:419-438, 1971.
5. Symposium on the Evaluation of the Safety of Food Additives and
Chemical Residues. Tox. Appl. Pharm. ^6:495-520, 1970.
6. The Effects on Population Exposure to Low LEvels of Ionizing Radiation
(Bier Report), In: The Report of the Advisory Committee of the
Biological Effects of Ionizing Radiation. National Academy of
Sciences, National Research Council, Washington, D. C. U. S.
Government Printing Office, Publication No. 0-489-797. 1972.
7. Interim Report on Extrapolation of Risk of Cancer from Animal Data
Committee to coordinate toxicology and Related Programs. Department
of Health, Education, and Welfare. Personnel Communication. May, 1974.
8. From Principles for Evaluating Chemicals in the Environment.
A report of the Committee for the Working Conference on Principles of
Protocols for Evaluating Chemicals in the Environment: Environmental
Studies Board, National Academy of Sciences - National Academy of
-------
DRAFT
DO NOT QUOTE OR CITE
Engineering, and Committee on Toxicology, National Research
Council. Washington, D. C. Chapter 5, 124-133, In Press (January,
1975).
ft- n
-------
DR/TT
DO HOT QUOTF ()$ ci f[
APPENDIX B
THE HEALTH EFFECTS OF VINYL CHLORIDE
A Compilation of Toxicologic, Clinical, and Epidemiologic Data
-------
su^:v71- cf to ¦c,lc".:c\l c-ta
Pata
1
ex-:,"
r-it^rs
Sccces
;e <
t-r5 .
per
j *v
Cone
lOLil
Hcse :
,r>..
-.- i*.
0hser/2t'c-s
Pa t^clcct
Von Cettirgen
(1955)
jabcr
Jecca-°.adu
,Janta
(19£2)
Ihe-i.Abstract
.ester
jreenfcerg
'da-s
,!So3>
\
Rat or
Ra-'u
Preda
Pbrodean
Joanof
Anca
VaIcztay
(ISSi)
Chen.Atstra
Grigorescu
Toba
(1S £6)
iem.Abstract
Hltjh
Hi^?an
Kunan
Hurjn
Hjr.an
H
F
82
73
fi2,r:o
jc.occ
? 5, CCO
c-'ver$ ex::=ed to pi,
Benzene, >*:
Produced s>_;tc_s of duziress, disorientation,
headace a-d i:v.-rir; sensation cn so'ss cf feet.
;l
0
83.3
166.7
250.0
3 3C.3
416.7
E^cod Dec-ease ir, catalase
Increase in peroxidase, indcphenoloxidase
and gluthat1-.jc-.e
Changes occurred during second year of work.
1/6 si i^tly di zzy
0/6 had any effects
1/5 s11c-1'/ d¦z zy
2/6 de*i-;:?ly dtzzy
5/c d'zzj, r.i^-. = =, blurred visicn ar.d heavirg
syrtrs stcrred after excos^re
6/5 .C2tej, o-e -1th persistant headaches
5C^ le/e1 of ro e*fe:t 1s 1.3*
No statr-e-.t ab:ut repeated expoj^-es
Decrease = ^s~a alb'.-in
Increased/C a-d ^"c i:: J-«n
Decrease ir/:/, -or se-'.- 1ipc;rot£
ins
PVC Workers
Contrq1,: Ctrer clinically ;
health
j peon.e
Decrease ic1"j 1 ireste-ase
Dec-ease m pse.de cholinesterase
Nor-al bl;cd catalase
f.'or—a 1 serj-- pynw.c acid
pcct'esis' VCVJ20 >chlcral + chloracetic acid (1).
^esjlts- (1) '•as fojr.d in £r,^ of exptl. people, but
in none of ccitrols.
Most of + f'rd-,rcs were in pecole exccsed 2-5 years.
In thesa cases, ^ - globulin is highe-,/^'- glob-jlin
Is 1c«er tran people with no (1) in urine.
'Capacity to retabolize (1) decreased after 2 years.
None reported
None reported
Ncne reported
None reported
(O
d
O
ZXj
-------
CP TQXSCOUjICAL cm;
Hu^an Data
2
J t' irs
Soecies S=>x
-rrls
'ars
967)
1 son
^ornick
tut
•aech
?P7)
-eeta
ewart
tchler
369)
Vyautseva
'70)
:tract
,1a
¦70)
ubllshed
Puran
Hunan M
Human
Hirran
Hunan
Hrs.
per
Day
F
-------
=-r-:-s
r-.-'rc
EYn.;.
trj.
per
I Tccdl
CencJ fcse
sufr/iiu rr c"L"r.;r;.L n-;,\
Hu'-'.n p.'
ObservJt^CPS
Dlnran
Cook
Water^cuse
Haqnuson
"1 tcheck
(1971)
Dodscn
Oln-an
Whlte^ouse
Nasr
Hacnuson
(1971)
Itraner
"utchler
(1971)
Hvi-ar
5011
21,513 "3i-
f-LTan
Hj-an
93
1-23
- I'p to 2p year
ears Experience
c ated with hand cl°an,n of
t Colye* i:5's.
; There aocsred ;0 |-e correlation het-een reactor
jdeaassirc tire and acro-csteoivs 1 s
All pat'erts had hcr'
-------
thors
SLW.RY CF TCXICC'-CjICAl DATA
HL"'AN CA iA
hxr^-s
Sogers S;x f:o. Hrs/Piv Days
EXPOSURE
Ccr.c.
P=-i-
Total Dcse
ps?i-days
CBSWATICr.S
PATHOLCGY
'erson
ier
5 72)
stract
-kowitz
.onald
:hiere
-zrer
:7Z)
:tract
e
ge
in
tman
73)
Human
Human
Human
13
Ages 29-52 Reactor clearer*
2-18 yrs. errploy-snt
Acroosteolysls
Had unique popular skin
lesions which have been
described only 1n PVC workers
Describe acrcostsolysis
Synptons. Incidence Is C32
trong workers
Latent period: 14-3^ years
fn 11 patients; 7 and 11
years in other 2 patierts.
Acro-osteolysis synptons.
P9nphS*"fil V0**?!
'77\rc.Tbc?eny {lew c:,"1:; "is
the first objective symptom
described in all patients;
lung fibrosis ori^inat*-^ »¦
portal systs-i, ta—^2
iirpaired lurg function,
102 irartality. This is tfia
first objective syrptom
-described
O
O
-------
surv^Y cf tox;"lo"i:;l data
Ku~an Oat3
5
E<5ns'.3-:
^r s
1 To;al
pe-
Cone "cse :
^ C •- s
S c c c i e s S-< *•-
?iv
Civs 1
-;n 1 D---n>VS
Observations
Pathol ccv
-steller
bach
ler
e
?e
_er
tnan
73)
HLiran
120
to^2I years
1,20 PVC workers were studied out of 45 with
suspected skin prcble-.s, because and possible fn
perform laporoscopy on 20. 30 to 55 vears old.
Liver enlarged 1n 13/20.
Pain tn Rt. upper atdcen In 2/20
Hyperlipidemia has been diagnosed 1n
1967 after 6 years in 1/20
Jaundice history ;n 1955 fcerore
exposure in 1953, liver dysfunction
was diaqrosed, no alcoholism.
Spleencregaly in 7/20.
Total bilirubin v,as>l ng/100 {which
1 s upper nomal lirit) in 3/20.
Bror.sulphaleir test was abnorral in
19/20 (>5J rete°ticn after 45
minutes).
SGftT was > 12 rll/rl in 17/20.
5GPT was elevated (15-30) in 14/20.
Alkaline phosrhatae? >as> 43 uLVl 1n 2/2
Fypothrcr,bocyte~ia (^15CxlnJ/-7-3) W3S
found 1^/20^
(O00* 10*/ii i'') in llr-
Pcro-ostyeolysis v.as seen in 4/20.
Vericose veins of escz'-acus in 3/20.
Liver hlstolccy- Collacen tra"sfcrration
of walls of sinusoids in 5,iZ.
Focal actlvaticn of Kusfer cells In 9/1
Focal fatty infiltration in 14/20.
Fibrosis of septa ard caosule
Intralobular aid portal spaces 1n
17/20.
15 additional blood oara-eters were
roriral.
9 immunological tests were dore once,
not repeated.
O
O
-TO
a
o
—H
¦m
CD
PC
m
-------
Authors
rpcsise
Cone.
S:°;'»s Sex So Hrs/djy da/s cr-
Cr T.
A-M^L cats
Total Cose
oy-ii /s
Von Oetttncer, Ca*;
('555)
(Review Article)
N3 NO N3
Cats NO NO <4
Cats ND N2 <4
Catj NO NO < 4
Cats NO NO 4
Cat:,
ND NO ND
Doss NO NO < 4
Ccjs ND NO 3
Dogs NO ND 3
NO NO
ico.cco to
130,OCO
18C.CC0
2co,c:o
2e:.c:o ts
300,CCO
NO NO
Rabiilts ND NO lmln. 1
Ccs'.
Mice ND ND 1 »iln. 1
1
7
for
lever-
• 1 tiks
170,CCO
86,CCO to
123,CCO
IOC.CCO
10,CCO
7 for 2C0.C30
seve--
il tals
Wee NO ND 10 mln. 1 245.CC0 to
: 295,CCO
6. Piss NO ND short 1 2C0.CC0 to
NO
<1,2C3
<30, COO
« 33.CCC
<43,c:: to
50,CCO
ND
118
< 12,CCO
475
tire
400,CCO
ND
cssrr.i-rcss
PATVOIOGY
VC ts prc-ptiy excreted by lurgs, 82: 1s eliminated
srter Inhalat'cn steps
Blocd VC corcentratton reaches 15-17 rg! '
This corce-tratlcn causes sare fntra-aurlcular
pressure redactisi as 13.CC0 ppn dlchlorcethylene.
3D.CC0 pp-ri ether
Cardiac tnsu'M; *5—/
Even this dees rat produce cc-plete cardiac failure
Blood levels are
-------
I
Authors
ANI^.S EIPC'3'J^
Cone. Total Cose
S:ec';s Sex '-o Hrs/dr/ da/s p:~ :cT.-da/;
Vo" Cettfr.gen
(1?55)
Revlev Article
Continued
Hastrc-atteo
Fisher
Christie
Oanzlqe*
(15:0)
Fisher
Christie
Danzlger
(I960)
G. Pigs ND NO 0.5-1
G. Pigs ND NO 0.5-1
S. Pigs ND NO 0 5-1
Mice NO 5 0.5
Rats ND 5 0.5
G. Pigs NO 5 0.5
1 100,000
1 5.CWO
TO
1"\ 1C0.CC0
U
Ririe- of anirsls and (Juration 200,CCD
of exposure sa~e as a^3ve
2,o:o to
4,000
100 to
200
2.CS3
4,160
tti-ie- of anlrals and du-atlon 3C0.CC0 6,250
of exposjre sar? as aio.e
Nu-ier of anlrals a-d cf--ailen 4C0.CC0
of eapcsjre sa~e as above
Torkelson (1) Rats
Oyea
3oe
(1951)
M 10
F 10
/5d/wlt\ SCO
(4.syc/
8.233
14.CC0
css-r^'.Arrcss
PATVQi.Qr.T
2
Oargerous to life
Higher concenfatlcns than this cause severe
lurg ede'-a and hjce'c-ia of liver and k1d-,ey
Order of toxicity Is ca-bon tetrachloride :~
>VC=s?ethyl chloride
Secue-.tlal effects v>ere- 1. Irrltatlcn,
2, Increased rotor activity, 3. twltchlrg,
4. treror, Inc:c-d1p>t!cn, 5. unconscious,
6. dee? narcosis. All ani-als recovered In
S minutes.
Hlce: Light lung
engorg-ent, Hdrey
jwel 1 lrgj ®ats and
G. Pigs, sare lusg
picture.
1/5 mice died afte- 30 nlrutes, sare
Jypto.-s as above i-t a:peared scorer.
Golnea pigs unstejdy for*Z3 mm. after
exposjre.
5/5 mice and 5/: rats died, 1/5 gu'r.ea
pigs died, 4/5 gul-ea pigs recorered 1n
25 minutes.
2/5 gulrea pigs died
Growth ard gross appearance *ere no—al.
Liver/tody we1g-it ratio ard absolute liver
weight larger than ccr.fol 1n raies.
Llver/bcdy we'.g-t a-,d absolute' liver
weight rot larrjr ;->t cc.-tro" In fe-ales.
Blood SCOT, SGr7, S<.N, a'.xilir.e pr.ospnatise
•ere norMl.
Lung engorge1-;-!. no
ede-a 1 r. all species.
One rat had fatty 1Iver.
11ver ar.d kidney was
congested, tracheal
•p 1 the 11 u.— da-agsd
Sa.re syrptcs, trjre
severe
Central lobular Hyer
degeneration.
Kidney tubular da-age.
o
C3
D
~
•>
n
-i
-------
EIPOSLSE
Co-c. Total Cos
-dl S°» f.': Krs/dav d:-s ::-i • oc-.dj (5
Tcrkelsen
l Oy!n .
Ro»e
(1961)
continued
(2«)
5
7
(5d/-k] 0
0
F
S
, 7
. II V 5"°/ (
/ i \ 1
Rats
M
12
7
R
12
7
138
to
G. Pigs
M
10
7
exposures
F
8
7
1n 204
Rabbits
days
H
3
7
(6.S cvonths)
K
3
7
Ccgs
H
1
7
200
8,050
M
1
7
to
Matched
B.'CO
con
trols.
both exposed and non- 5d/rt
exposed g-oups
(2b) Sire protocols 100 4.0C0
to
4.2CO
- u« n
: 11 j
C3S:
PATHTLCGr
Control dil-jls
All groups were rcr-
-------
a.\;u;ls exdosu£
Cone.
5:»:'»s S*x s3 H-s/dw d>,s ::-
/ Rats
Rats
M
M
H
M
H
N
H
H
F
S. Pigs «
F
Rabbits H
F
Dags
5
S
S
5
5
5
5
5
24
12
12
1
3
1
1
Watered cont-ols, exposed
jrd u-exposed groups.
Sher-an
rats
'10
2
0-2
ND
2
0-2
fiD
2
0-2
hD
2
0-2
NO
1
5 n1n
42 Bin
NO
2
5d/wk
2C0
for
2CO
6 5
200
iro.itfcs
2C0
as
ICO
above
ICO
100
ICO
130
exposure
In
169
days
50,000
60.CC0
70,c;o
ico.cro
15O.CC0
150,COO
Total Case
g:~-iivs
casEn-.-
':C'.S
t,ver/b;<;J' "e'S'it ratio lar;er than controls, not statistically significant
1,150 l^.r/tody *;1cht ratio sa-e as centrals
3/ 3 ¦
2.3C0 Ifver/bedy we1Sht ratio higher than controls, not statistically significant
575 Norral In all resoacts
265 • •
All parameters norrjl In all species.
0-1,160 u:de-ate Wsxlcitlo-i, rlshtlnc reflex lost.
0-5,C30 IV? ir:e-;e 1r.to
-------
f-irs
Scccies
Sex
ster (2)
Sher-an
u
9
eer.berg
rats
ns
563)
it'd.
F
9
M
9
F
9
(3)
Shennan
K
75
rats
F
15
M
15
F
15
EXsnS'J-i
r s..
Total
pe-
| Ccnc
Dose
0a /
Cavs 1 o;-1
DO-I-I^'S
SUMMARY OF TOXICOLCriOM DATA
ArvT-al Data
Observations
13
Sa-e
100,00Variable; After antral deaths, replace-ents were nade in
£c.-.i-ters TVo r>]es sur.'i/ed all 15 exposures.
};P:rainT-g ar.irals and reolace~ents survived an
en
80,CC^
e
-------
Sirr.lRY CF TOXICOLOr.rCAL D-TA
An 1 ~a1 Data
EXFHSiPE
.'t>crs
Secies
Sex
V'o
1
hrs.
cer
"a v
Davs
Cere
0
To:a1(
Hess
D:--Day<
Observations
Pithol 03V
ster (4)
eenberg
jrs
353)
it'd.
Sherman
rats
M
F
M
F
5
5
5
5
*8
8
8
8
19
19
19
19
50,039
50,000
0
0
317,c:o
317,000
0
0
|i
, :;o rcrtal i ty.
j|0n days 1--, ani.-als lost weight, showed
, neuorclocical sy~2t:.~s.
sjCn days 4-19, ram was no—al.
tjSerum trysailrase, h:-atccr1t, and prothrcraln
jtlrres were Por~al.
;Wh1te and red cell counts were lc«er than controls.
Hair: all 5 rales had thin hair ar.d scaly tails;
females and controls were r.orral.
L1ver/tody weight ratio-was higher tnan controls.
Control am-als.
jControl anl.rals.
Gross organ appearance was sa~e as
controls.
Liver pathology showed congested
cells.
Liver parasitic cysts seen in all
anlirals.
N
V
J
O
o
zz:
o
-•i
o -;cr>
» m n
r-
cr.
-J-
<—>
-------
SUN'ARy OF TOXICOLO'-,ICAL DATA
Animal Data
7
EXPOSURE
'Jthors
So,
¦lo
jebler
Rats
ND
1964)
Mice
fID
bstract
G.PIgs
ND
Mice
ND
iz1n
Rabbits
ND
1 okhova
1968a)
jstract
~z1n
Rabbits
no
'okhova
~6flb)
jsiract
zin
Chin-
NO
okhova
chilla
969a)
rabbits
¦stract
z1n
Rats
ND
okfova
969b)
stract
>
\A
fin
no
no
NO
ND
ND
Hrs.
per
^ V
2
2
2
0.5 mi
"chroi
I Cone
Oavs i D-n
ND
167
(5.5
iros.) 3,900
100
100
100
jtes
tc"
5,000
15.0C0
50,000
Mstanc
0-25ct
3,500
3,900
150
8 to ii
150
5 months)
3,500
to
Total
Hose '
TOn-P;iys
Observations
41 ,600'l Mo effect at 5,000 and 150,000 ppm.
125,000[!'At 50,0(10, aninals were hyperactive, but returned
415,000 1 to norral after exDosure
ND
ND
ND
200
to
300
Anirals sorayed with a shellac-based hair spray
8ra1n electrical activity chanqes- Appearance of
beta waves (30 Hertz1 in anterior and posterior
hypothalmus along with circulatory changes.
Decreased heart rate, arrhythmia
Decreased ECR voltage
Decreased duration of systole
Reduced blood flow. Increased arterial pressure.
After 20 days, blood adrenaline rose from 3.5 /\gnt
to 6.15 i\ qr*, at 40 and irore days, It was 6.6 jjgn?
Posterior hyoothalmus electrical activity also
chanaed. This is the direct cause of hypertension.
Disrupted cardiac work rhythm. Bradycardia and
arrhythma. Reduced relative duration of I-II and
T-II sound intervals.
Relative duration of np.S conplex did not chanqe.
After 15 days recovery: cardiac activity rhythm
returned to noma!, but the duration of the sound
Interval remained below initial levels for another
15 days.
Therefore, rrax. permissible VC concentration Is sign
cantly less than .03 mg/1 (12 ppm).
Pathology
Ho histological damage
No change In tung histology
Altered ^waves 1n EEG fron posterior
hypothalmus. Potentials from anterior
and posterior hypothalmus Increased by
18-302 and 70-852 respectively.
fl-
O
O
O
yO ^
^ r"°
' CD
—*
m
O
£2
I
m
-------
surivw OF TOa ICOLOG [CAL DATA
Animal Data
^utu;rs
Clapp
Kaye
Younq
(1969)
Abstract
MoT a
[1970a)
/lola
! 197.0b)
'ioti
Igottl
aputo
1971)
*c-:cies Se>
fb
Rats
Mister
Rats
Rats
Wister
300 qm
Rats
Wister
fin
NO
25
25
EXPOSURE
fr s
per
Cav
90
26
25
260
(5 da>
aer wk
for 12
nonths)
4
5day/w
1
5day/w!
I Cone
Days I ocn
Sub-
futane
30,000
0
10,000
260
260
30.00C
0
Total
Hose '
Dom-Pavs
ND
us
l ,3noxio^
Cbser/ations
Pathcloav
Urine contains allylrercaDturic acid and 3-hydroxy-
• propylmercaptun c acid. These compounds arise by
the reactions of ally! compounds with Glutathiones.
Animals sliahtly slesny during exposure.
Gross behavior deteriorated after 10 months.
13/50 died of cardio-respiratory complications.
2/50 died of bleedinq 1n the peritoneal cavity.
No mention of skin tumors.
417
1300xl03
0
Distribution of VC 1n tissues:
Red cells had much more VC than serum—high
variation
VC Is In urine, but major quantity Is lost via
fyQ] falls rapidly In first hour in expired air,
urine, and brain, liver, kidney. After 3 hrs.
VC is measurable.
lunq
bloo<
no
None observed
Kost animals had pathological Involveme
of brain, liver, kidney, thyroid.
Severe proliferation of cartilege and
bone abnormalities In small metatarsal
bones.
Severe tissue degeneration In brain anc
liver and thyroid.
Connective tissue Invaded small arterle
In feet.
Enlarged, proliferating Kupfer cells 1n
liver.
None observed.
Controls showed no tumors. Almost all
exptl. aningls developed skin and lun
tumors. Very few bone tumors; when s
they were 1n all 4 extrer.ities.
651-70% of turors were skin tumors near
parotid and subraxillary alands
Frequencies: SKIN LU'lGS BONE
26/26 16/26 16/26
Luna tumors were glandular.
New cartilege and subsequent osslflcatl-
tn 4 extremetles.
Hard mass first seen after 10 months
exposure.
v&>
'*h
r
-------
> SUGARY OF TO XI CD LOGICAL DATA
Animal Data
EXPOSURE
'thcr;
fccci'es
S"x
r:n '
hrs.
per
Davs
Cone.
opm
Total,
Dose '
D3r-0iy<;
1
! Observations
Pa tholoay
asalaev
azin
ochetkov
1972)
bstract
Rabbits
Rats
tlD
ND
NO !
f!D
NO
ND
6 nos
(13C
to
180 -
! ~r\
m
o
ZO
O
—4
m
-------
Animal Data
ffOi li'O
A.U L
Scecies
S*»x
no
Hrs/Ow
Oava
conc.
Don
total dose
pr-'-d*1 va
Survivors
Liver Zyvbal Nephro-
Total Anqioaarcocws Sarcocvss Blaatorjs
ftaltonl 197-1
Rats
Sprague-
Davley
M
F
309
268
4
5da/wk
633
10,000
6,000
2,500
300
230
30
0
«icso
-------
¦"DRAFT:
TK3¦
LIS! OF REFERENCES
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to vinyl chloride vapor: breath nnalysis and continuous air sampling.
American Industrial Hygiene Association Journal, Volume 30, pp. 537-544.
1969.
Basalaev, A. V., A. N. Vazin and A. G. Kochetkov. Pathogenesis of
changes developing due to long-terra exposure to the effect of vinyl
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Clapp, J. J., C. M. Kaye, and L. Young. Metabolism of allyl compounds
in the rat. Biochem. Journal 114 (1), pp. 6-7. 1969.
Dinman, B. D., W. A. Cook, W. M. Whitehouse, H. J. Magnuson, and T.
Ditcheck. Occupational Acroosteolysis: I. An Epidemiological Study.
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Dodson, V. N., B. D. Dinman, W. M. Whitehouse, A. N. M. Nasr, and
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of the blood in workers exposed to toxic substances (benzene, chlorobenzene,
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Harris, D. K. and W. G. F. Adams. Acroosteolysis occurring in men
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5567, pp. 712-714. Illus. 1967.
Juhe, S., C. E. Lange, G. Stein, and G. Veltnian. Uber die sogenannte
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£ "J
-------
^'Lester, D.', L. A "Greenberg",and ~U'. :"R:' AdarasT^JEff ects "of single and"-' -
—'repeated-exposures of-humans "nnd-rats to- yiny-1 -chloride.-"American—-V —~-
r>~Indu8trialr^Hvgiene'^Aasocia^i.on^'Jqurpal,y-zppf>CT»^26S-2J.1^-MAy^-l»inp ,.L _
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—of vinyl chloride. Presented at OSHA vinyl-chloride-fact-finding
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Markowitz, S. S., C. 'j.'McDonald, W. Fethiere'Vnd M. S. Kerzner.
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^ " ^ ' " ~~ ~ ~ -X~z " - - ' - _ ' - ^ .
—Ma r a t el ler-^- H **"«J-/~'~Ghrondc-1 oxi e*-live r- dainago-=ii\i -wo r ke-r s~ engaged—i«—
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1'Mastromatteo, E., M.D., kV M.'Tisher, H."Christie," and'IL Danziger.^"'"
j:nAa?-?-?lon toxicity of vinyl chloride to laboratory animals. 2/f '
American Industrial Hygiene Association-JournaTVoTun 1 e*"2T7^ o 7 'Ifc*Eober,' v
"I960.
= i- —¦V-' =— —
— Meyerson, L. B.'and G. C." Meier. '"Cutaneous lesions in-acrooBteolysis,--- - -
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7 Torkelson, T. R.,7F.'0yen, ancry^. Rotie. "^The" toxic ity"~bf vinyl"""1" "J " l~
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-American Industrial Hygiene Association Journal, Volume 22, No." 5, p'p".-'"r~='-
;_354-361. 1961. ^ ^ - .. -..-.5 ---•
-rVazin, A. NT- and.-E. ~L.r-Plokhova.-~ Great-ion-of-an experiment a 1- modei^^jT_III__
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Vazin, A. "N., and E.^I. PlokhovaT - Pathogenic effect of" chronic exposure-"
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L"^ni?il E* Flokliova.'' Changes in'Ll.e" cardiac activity of rats " '
¦-"chronically exposed' to'Vinvl' chloHde"vnpdfsT- Farmalcol-'Toksikolr~ =-,-1;
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_ .Viola, P. L.i. Pathology of _vinyl_ chloride. _ ;Mcd^icina del_I>avoro, Volume"*"
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^_Viola, P. Li.^.,The.tv.inyl^Cbilorj,dardisease. ^(unpublished translation^.
^Z^ummer,, 1970. . _ j - r.-"^ :T"""! - 1
"»*r
1 — •! .'I. t'l I*' ^ '' - ' '¦ ¦¦ m ¦-¦ "H-^1 ¦ T t mm r ^.
Viola, P. L., A. Bigotti, and A. Caputo. Oncogenic response of'rat --- » - " .
skin, lungs, and bones to vinyl chloride. 'Cancer Research, Volume 31, " ' ¦
pp. ^516-522, May. 1971... -^ = .. ^-- - - .
d- ft
-------
i • it . .1- _ .^ct —-i.'J.-: - / , ." I* j, " DR/\FT
Von Oettingen, W. F., M.D. the haiogenated aliphatic, olefinic,
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• v
_ Wilson, R. H., W. E. M^CoraickT "cT fT Tat urn, and" J." L." Creech'.'
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