United States Office of Health and EPA-600/6-82-003
Environmental Protection Environmental Assessment January 1982
Agency Washington DC 20460 x» ,
C > !
Research and Development
Carcinogen DRAFT
Assessment of Coke
Oven Emissions
2,,y
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EXTERNAL REVIEW DRAFT
CARCINOGEN ASSESSMENT
OF
COKE OVEN EMISSIONS
Roy ETATbert, M.D.
Chairman
PARTICIPATING MEMBERS
Elizabeth L. Anderson, Ph.D.
Larry D. Anderson, Ph.D.
Steven Bayard, Ph.D.
David L. Bayliss, M.S.
Chao W. Chen, Ph.D.
Maragaret M. L. Chu, Ph.D.
Herman J. Gibb, B.S., M.P.H.
Bernard H. Haberman, D.V.M., M.S.
Charal ingayya B. Hiremath, Ph.D.
Robert McGaughy, Ph.D.
Dharm V. Singh, D.V.M. , Ph.D.
Nancy A. Tanchel , B.A.
Todd W. Thorslund, Sc.D.
Vicki Vaughan-Dellarco, Ph.D.*
*Reproductive Effects Assessment Group
DRAFT
DO NOT QUOTE OR CITE
This document has been reviewed and approved by the Chairman and staff
of the Carcinogen Assessment Group, Office of Health and Environmental
Assessment, U.S. Environmental Protection Agency. It has not been
formally released by the EPA and should not at this stage be construed
to represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
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PREFACE
The Carcinogen Assessment Group (CAG), located in the Office of Health and
Environmental Assessment of EPA's Office of Research and Development, is a
small group of scientists who perform an advisory assessment function for
EPA's regulatory offices. The CAG analyzes existing scientific data and
furnishes the regulatory offices with an evaluation of the carcinogenicity and
levels of carcinogenic risk associated with chemicals in various exposure
situations, as best can be determined from currently available scientific
data.
The CAG reports are prepared primarily for internal Agency use in response
to requests from the EPA regulatory offices. The scope of each evaluation
varies, depending upon the nature of the request. Evaluations range in
completeness from brief memoranda to extensive reports and are used by the
regulatory offices for decision making, as appropriate. The reports are
revised and updated based on regulatory office needs and the availability of
resources.
This document was prepared at the request of the EPA Office of Air Quality
Planning and Standards.
U,S. Environments/ ^~~-.-
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CONTENTS
I. Summary 1
Qualitative Assessment 1
Quantitative Assessment 5
II. Introduction 6
III. Metabolism 12
Polynuclear Organic Matter (Polynuclear Aromatic Hydrocarbons
and Polynuclear Aza-Heterocyclic Compounds 12
Aromatic Amines 22
Other Aromatic Compounds 23
Trace Elements 24
Other Gases 26
IV. Mutagenicity and Cell Transformation 27
Studies Evaluating Solvent-Extractable Organics of Coke Oven
Door Emissions 27
Studies Evaluating the Complex Material from the Coke Oven
Collecting Main 31
Studies Evaluating Solvent-Extractable Organics of Air
Particulates Collected on Top of Coke Ovens 34
Studies Evaluating Urine Concentrates of Coke Plant
Workers 46
Mutagenicity of Individual Components Identified
in Coke Oven Emissions 48
Summary and Conclusions 51
Cell Transformation 52
V. Toxicity 54
Acute Toxicity of Coal Tar 54
Subchronic and Chronic Toxicity of Coal Tar Aerosols 54
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VI. Carcinogenicity 64
Human Epidemiology Studies 64
Animal Studies 113
Carcinogenicity of Coke Oven Emission Components 140
VII. Unit Risk Estimate 144
Mathematical Model Relating Exposure to an Environmental
Hazard to Probability of Death Due to a Specified Cause . . .144
Model Applied to Effects of Coke Oven Emissions on Respiratory
Cancer Rates of Nonwhite Male Steelworkers 147
Estimation of the Unknown Parameters 1,6 152
Evaluation of the Goodness of Fit of the Model 155
Estimation of the Unit Risk for Coal Tar Pitch Volatiles. . . .155
Additional Potential Problems and Sources of Error Associated
with the Unit Risk Estimate 162
VIII. References 163
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ACKNOWLEDGMENTS
The Carcinogen Assessment Group acknowledges the contributions of Dr.
Robert Bruce, Environmental Criteria and Assessment Office, Research Triangle
Park, North Carolina, and Mr. Joseph Santodonato, Syracuse Research
Corporation, Syracuse, New York, in the preparation of this document.
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I. SUMMARY
The purpose of this document is to evaluate the carcinogenicity of coke
oven emissions and to develop a respiratory cancer unit risk estimate, which
is the cancer risk from a lifetime exposure to 1 ug/m-^ concentration of coke
oven particulates.
QUALITATIVE ASSESSMENT
The production of coke by the carbonization of bituminous coal leads to
the atmospheric release of chemically-complex emissions from coke ovens. The
toxic constituents include both gases and respirable particulate matter of
varying chemical composition. Greatest attention has been focused on the
toxic effects of the particulate phase of the coal tar pitch volatiles (CTPV)
emitted from coke ovens, principally because this fraction contains polycylic
organic matter (POM). In addition to POM, there is concern over the potential
carcinogenic and/or cocarcinogenic effects of aromatic compounds (e.g.,
3-naphthylamine, benzene), trace metals (e.g., arsenic, beryllium, cadmium,
chromium, lead, nickel), and gases (e.g., nitric oxide, sulfur dioxide), which
are also emitted from coke ovens.
Extensive epidemiological studies of coke oven workers by Lloyd (1971),
Redmond et al. (1972), Redmond et al. (1976), and Redmond et al. (1979) found
that workers exposed to coke oven emissions were at an increased risk of
cancer. A dose-response relationship was established in terms of both length
of employment and intensity of exposure according to work area at the top or
side of the coke oven. The relative risk of lung, trachea, and bronchus
cancer mortality was 6.94 among Allegheny County, Pennsylvania workers who had
5 or more years of experience and worked full-time topside at the coke ovens.
By comparison, side oven workers employed more than 5 years had a relative
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risk of 1.91, while nonoven workers employed more than 5 years had a relative
risk of 1.11. Deaths from malignant neoplasms at all sites were also found to
be dose-related among the Allegheny County workers. Among non-Allegheny
County coke oven workers employed more than 5 years, the relative risk of
cancer of the lung, trachea, and bronchus was 3.47 for full-time topside, 2.31
for mixed topside and side oven, and 2.06 for side oven. Although adequate
smoking data were not available for either the Allegheny County or
non-Allegheny County workers, it is not likely that differences in smoking
habits could be of sufficient magnitude to negate the dose-response effect
that was found. In addition to elevated mortality from cancer at all sites
and elevated mortality from cancer of the lung, trachea, and bronchus, there
was significant (P < 0.05) excess kidney cancer mortality (relative risk of
2.37) and prostate cancer mortality (relative risk of 2.45) among Allegheny
County workers. A significant (P < 0.05) excess of prostate cancer mortality
was found for the nonwhite non-Allegheny County workers (relative risk of
2.45).
Sakabe et al. (1975) observed a significant (P < 0.05) excess of lung
cancer deaths (relative risk of 2.37) among retired iron and steel coke oven
workers in Japan when compared to expected, which was derived from general
population statistics. The strength of the association is weakened, however,
by the lack of adequate smoking data.
British studies of coke oven workers did not show the magnitude of risk
that the American studies or the Sakabe et al. study did. Davies (1977, 1978)
found no excess mortality for coke oven workers when compared to the general
population. However, a short observation period and the lack of evaluation
according to intensity of exposure by occupational work area are shortcomings
of this study. Reid and Buck (1956) did not find an excess of respiratory
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cancer among British coke oven workers. They did find an excess in mortality
from cancer, other than respiratory cancer, however. The authors' failure to
define the study population, to adequately address latent effects, and to
provide sufficient information on how expected deaths were derived, make it
difficult to draw conclusions from this early study. Collings (1978) found an
increase in lung cancer deaths among British coke oven workers; the increase
was not statistically significant however. The period of observation was
short (only 9 years), and Ceilings did not study the workers by work area,
which might have detected a mortality difference by exposure.
Extracts of a topside coke oven sample and a sample obtained from a coke
oven collecting main were found to have skin tumor initiating activity in
initiation-promotion studies in SENCAR mice (Nesnow et al. 1981). The coke
oven main extract sample also induced skin tumors when topically applied to
SENCAR mice as a complete carcinogen or as a promoter following initiation
with benzo[a]pyrene (Nesnow et al. 1981). Nesnow. (1980) reported no
initiating effect of topside coke oven sample extract in an
initiation-promotion study in C57BL6 mice; however, this mouse strain was
resistant to the positive control agent benzo[a]pyrene. The above studies on
topside coke oven sample extract are weakened by contamination of the sample
with particulates from ambient air. Coal tar, a condensate from coke oven
emissions, has been found to be a skin carcinogen in several animal studies.
Coal tar aerosols have been found to cause tumors of the lung in mice (Morton
et al. 1963, Tye and Stemmer 1967, Kinkead 1973, MacEwen and Vernot 1976).
Numerous animal studies have found constituents of coke oven tar and coke oven
emissions to be carcinogenic.
Mutagenicity tests on the complex mixture of solvent-extracted organics of
coke oven emissions were positive in bacteria. A complex mixture from the
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coke oven collecting main was mutagenic in bacteria and mammalian cells in_
vitro. In addition, a number of components identified in coke oven emissions
are recognized as mutagens and/or carcinogens. Cell transformation was found
in Balb/C 3T3 mouse embryo fibroblasts and Syrian hamster embryo cells treated
with solvent-extracted organics of air particulates collected topside of a
coke oven; however, these studies involve possibly significant contamination
of the sample with ambient air particulates.
Based on the above information, the following conclusions can be drawn:
1) Coke oven workers have been found to be at an excess risk of mortality from
cancer at all sites, lung cancer, prostate cancer, and kidney cancer.
2) Sample extract from a coke oven main and coal tar, a condensate of coke
oven emissions, were found to be carcinogenic in animal skin painting studies.
Animals exposed to coal tar aerosol developed lung tumors. 3) Sample extracts
from coke oven topside sample and a coke oven main initiated tumor formation
in initiation-promotion studies in mice. 4) Coke oven door emissions were
found to be mutagenic in bacteria. 5) Numerous constituents of coke oven
emissions are known or suspected carcinogens. The Carcinogen Assessment Group
concludes that coke oven emissions are carcinogenic.
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QUANTITATIVE ASSESSMENT
A mathematical model has been developed to predict the lifetime
probability of cancer death due to a continuous exposure to a carcinogen.
The "minimum initiation time" and potency parameters of the model are
estimated using extensive epidemiological data concerning nonwhite
steelworkers exposed to coal tar pitch volatiles. These parameter estimates
are then used to predict the lifetime probability of respiratory cancer death
due to a lifetime exposure of 1 ugm/m3 of coal tar pitch volatiles. This
estimate was determined to be 0.9 x 10-3, with a 95% confidence interval of
0.5 x ID'3 to 1.5 x 10-3.
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II. INTRODUCTION
Coke is a porous, cellular carbon residue produced from the carbonization of
soft (bituminous) coal and used primarily in the steel industry's blast furnaces
to make iron that is subsequently refined into steel. As of October 1979, the
United States metallurgical coke industry was composed of 34 companies with 61
plants in 19 states. Of the industry's 61 plants, 46 are operated by iron and
steel companies that produce coke primarily for use in their own blast furnaces.
They are customarily referred to as "furnace" plants, in contrast to the
industry's 13 "merchant" plants that generally sell their coke on the open
market to foundries and other consumers. Throughout both of these industry
segments, the by-product, or slot-oven process, is employed to produce what is
termed "oven" coke. Currently, 93% of its output is accounted for by furnace
plants and 7% by merchant plants. An alternative coking method, the beehive
process, is employed by only two plants to produce relatively minor quantities
of "beehive" coke, most of which is marketed for blast furnace use. The basic
difference between the by-product coke oven and the beehive oven is that the
former recovers vapors and other by-products from the coking process, while the
latter does not. In 1979, the 59 by-product coke oven plants consisted of 199
batteries containing 11,413 ovens that produced 63,377,505 tons of coke (Hogan
and Koelble 1979).
A typical by-product oven is 10 to 22 feet high, 36 to 55 feet long, and
approximately 18 inches wide. A coking facility generally contains several
batteries and each battery consists of 20 to 100 ovens. The coking cycle begins
with the introduction of coal into the coke oven (charging) by means of a
mechanical Tarry car which operates on rails on top of the battery. During
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the charging process the lids on the charging holes are removed and the oven is
placed under steam aspiration. This operation limits the escape of gases from
the oven during charging so that they can be collected in the by-product gas
collector main for subsequent processing. Following the heating of the coal at
1046°C (1900°F) to 1100°C (2000°F) for 16 to 20 hours, the doors on each side of
the oven are removed, and the coke is pushed by a mechanically-operated ram
into a railroad car called the quench car. The quench car is then moved down
the battery to a quench tower where the hot coke is cooled with water.
The reactions taking place in the coke oven can be characterized in three
parts (OSHA 1976). In the first step, coal breaks down at temperatures below
700°C (1296°F) to primary products consisting of water, carbon monoxide, carbon
dioxide, hydrogen sulfide, olefins, paraffins, aromatic hydrocarbons, and
phenolic- and nitrogen-containing compounds. The second step occurs when the
primary products react as they pass through the hot coke and along the heated
oven walls at temperatures above 700°C (1296°F). This results in the formation
of aromatic hydrocarbons and methane; the evolution of hydrogen; and the
decomposition of nitrogen-containing compounds, hydrogen cyanide, pyridine
bases, ammonia, and nitrogen. The third step results in the formation of hard
coke by the progressive removal of hydrogen.
Gases evolved during coking leave the coke oven through the standpipes, pass
into goosenecks, and travel through a damper valve to the gas collection main
that directs them to the by-product plant. These gases account for 20 to 35
percent by weight of the initial coal charge and are composed of water vapor,
tar, light oils, heavy hydrocarbons, and other chemical compounds (Coy et al.
1980).
The raw coke oven gas exits at temperatures estimated at 760° to 870°C and
is shock cooled by spraying recycled "flushing liquor" into the collection
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main. This spray cools the gas to 80° to 100°C, precipitates tar, condenses
various vapors, and serves as the carrying medium for the condensed compounds.
These products are separated from the liquor in a decanter and are subsequently
processed to yield tar and tar derivatives, including pyridine, tar acids,
napthalene, creosote oil, and coal tar pitch. The gas is then passed either to
a final tar extractor or an electrostatic precipitator for additional tar
removal. On leaving the tar extractor, the gas carries three-fourths of the
ammonia and 95 percent of the light oil originally present when leaving the
oven.
The ammonia is recovered either as an aqueous solution by water absorption
or as ammonium sulfate salt. Ammonium sulfate is crystallized in a saturator
which contains a solution of 5 to 10 percent sulfuric acid and is removed by an
air injector or centrifugal pump. The salt is dried in a centrifuge and
packaged.
The gas leaving the saturator at about 60°C is taken to final coolers or
condensers, where it is typically cooled with water to approximately 24°C.
During this cooling, some naphthalene separates and is carried along with the
wastewater and recovered. The remaining gas is passed into a light oil or
benzol scrubber, over which is circulated a heavy petroleum fraction called wash
oil or a coal-tar oil which serves as the absorbent medium. The oil is sprayed
in the top of the packed absorption tower while the gas flows up through the
tower. The wash oil absorbs about 2 to 3 percent of its weight of light oil,
with a removal efficiency of about 95 percent of the light oil vapor in the gas.
The rich wash oil is passed to a countercurrent steam stripping column. The
steam and light oil vapors pass upward from the still through a heat exchange to
a condenser and water separator. The light oil may be sold as crude or
processed to recover benzene, toluene, xylene, and solvent naphtha.
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After tar, ammonia, and light oil removal, the gas undergoes a final
desulfurization process at some coke plants before being used as fuel. The coke
oven gas has a rather high heating value, on the order of 20 MJ/Nm3 (550
Btu/scf). Typically, 35 to 40 percent of the gas is returned to fuel the coke
oven combustion system, and the remainder is used for other heating needs.
Typically, one ton of coal will yield the following products:
Blast Furnace Coke 545-635 kg
Large Coke Particulates 49-90 kg
Coke Oven Gas 285-345 m3
Tar 27.5-34 1
Ammonium Sulfate 7-9 kg
Ammonium Liquor 5-135 1
Light Oil 8-12.5 1
Human exposure to coke oven emissions occurs as a result of emissions
released during the charging, coking (door, topside port, and offtake system
leaks), and pushing operations. During these operations large quantities of
sulfur dioxide, organic vapors, particulates, and coal tar pitch volatiles
adsorbed to particulates, can be emitted to the atmosphere. A detailed list of
constituents found in coke oven emissions is given in Table II-l.
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TABLE II-l. PARTIAL LIST OF CONSTITUENTS OF COKE OVEN EMISSIONS
(U.S. EPA 1978a)
POLYNUCLEAR AROMATIC HYDROCARBONS
Anthanthrene
Anthracene
Benzindene
Benz[a]anthracene
Benz[b]f1uoranthene
Benzo[ghi]fluoranthene
Benzo[j]fluoranthene
Benzo[k]fl uoranthene
Benzofluorene
Benzo[a]fluorene
Benzo[b]fluorene
Benzo[c]fluorene
Benzo[c]phenanthrene
Benzo[ghi]perylene
Benzo[a]pyrene
Benzo[e]pyrene
Benzoquinoline
Chrysene
Coronene
Dibenz[a,h]anthracene
Dibenzo[a,h]pyrene
Di hydroanthracene
Dihydrobenzo[a]fluorene
Dihydrobenzo[b]fl uorene
Di hydrobenzo[c]f1uorene
Di hydrobenz[a]anthracene
Dihydrochrysene
Di hydrofl uoranthene
Dihydrofluorene
Dihydromethylbenz[a]anthracene
Dihydromethylbenzo[k and b]fluoranthenes
Dihydromethylbenzo[a and e]pyrenes
Di hydromethylchrysene
Dihydromethy!triphenylene
Di hydrophenanthrene
Dihydropyrene
Di hydrotri phenylene
Dimethylbenzo[b]f1uoranthene
Dimethylbenzo[k]f1uoranthene
Dimethylbenzo[a]pyrene
Dimethylchrysene
Dimethyltriphenylene
Ethyl anthracene
Ethylphenanthrene
Fluoranthene
Fluorene
Indeno[l,2,3-cd]pyrene
Methy!anthracene
Methylbenzo[a]anthracene
Methylbenzo[a]pyrene
Methylbenzo[gh i]perylene
Methylchrysene
Methylfluoranthene
Methylfluorene
Methylphenanthrene
Methylpyrene
Methy!triphenylene
Octahydroanthracene
Octahydrofl uoranthene
Octahydrophenanthrene
Octahydropyrene
Perylene
Phenanthrene
Indeno[l,2,3-cd]pyrene
Pyrene
Triphenylene
POLYNUCLEAR AZA-HETEROCYCLIC COMPOUNDS
Acridine
Benz[c]acridine
Dibenz[a,h]acridine
Dibenz[a,j]acridine
AROMATIC AMINES
crNaphthylamine
3-Naphthylamine
TRACE ELEMENTS
Arsenic
Beryllium
Cadmi um
Chromium
Cobal t
Iron
Lead
Nickel
Selenium
(continued on the TOM owing page)
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TABLE II-l. (continued)
OTHER AROMATIC COMPOUNDS OTHER GASES
Benzene Ammonia
Phenol Carbon disulfide
Toluene Carbon monoxide
Xylene Hydrogen cyanide
Hydrogen sulfide
Methane
Nitric oxide
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III. METABOLISM
A rather brief and general discussion of the metabolism of the classes of
coke oven emission components shown in Table II-l is presented in this
section. The basis of discussion, particularly for classes besides
polynuclear organic matter, are reviews on metabolism in the cited documents.
As shown in Table II-l, coke oven emissions can contain a wide array of
chemical components. Therefore, the toxicologic significance of any single
component or class of components to the carcinogenic potential of coke oven
emission samples is difficult to estimate without knowledge of the chemical
composition of the samples, as well as the amount of each component absorbed
and metabolized by humans. Additionally, the metabolic profile of a coke oven
emission sample with respect to its components considered together as a group
would appear to be quite difficult to determine. Nonetheless, evidence is
presented herein to indicate that chemicals or classes of chemicals described
in Table II-l can contribute to the carcinogenic potential of coke oven
emissions via metabolism to active carcinogenic agents.
POLYNUCLEAR ORGANIC MATTER (POLYNUCLEAR AROMATIC HYDROCARBONS AND POLYNUCLEAR
AZA-HETEROCYCLIC COMPOUNDS)
Polynuclear organic matter (POM) are metabolized via enzyme-mediated
oxidative mechanisms to form reactive electrophiles (Lehr et al. 1978). For
many of the POM, certain "bioactivated" metabolites are formed that have the
capability for covalent interaction with cellular constituents (i.e., RNA,
DNA, proteins) and ultimately leading to mutation and carcinogenesis.
The obligatory involvement of metabolic activation for the expression of
POM-induced carcinogenesis has prompted the investigation of POM metabolism in
numerous animal models and human tissues. From these studies has emerged an
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understanding of the general mechanisms involved in POM bi'otransformation. It
is now known that POM are metabolized by the cytochrome P-450-dependent
microsomal mixed-function oxidase (MFO) system, often designated aryl
hydrocarbon hydroxylase (Conney 1967, Marquardt 1976, Sims 1976, Gelboin et
al. 1972). The activity of this enzyme system is readily inducible by
exposure to various chemicals and is found in most mammalian tissues, although
primarily studied in the liver (Bast et al. 1976, Chuang et al. 1977, Andrews
et al. 1976, Cohn et al. 1977, Wiebel et al. 1975, Grundin et al. 1973,
Zampaglione and Mannering 1973). The MFO system is involved in the metabolism
of endogenous substrates (e.g., steroids) and the detoxification of many
xenobiotics. However, the MFO system also catalyzes the formation of reactive
epoxide metabolites from certain POM, possibly leading to carcinogenesis in
experimental mammals (Sims and Grover 1974; Selkirk et al. 1971, 1975; Sims
1976; Thakker et al. 1977; Levin et al. 1977; Lehr et al. 1978). A second
microsomal enzyme, epoxide hydrase, converts epoxide metabolites of POM to
vicinal glycols, a process which may also play a critical role in carcinogenic
bioactivation. Figure III-l presents a schematic representation of the
various enzymes involved in activation and detoxification pathways for B[a]P.
At present this also appears to be representative of the general mechanism for
POM metabolism.
A discussion of the metabolism of POM in mammalian species, including man,
is best approached by examining in detail the chemical fate of the most
representative and well-studied compound in the POM class, namely B[a]P. The
metabolism of B[a]P has been extensively studied in rodents (for a review, see
Yang et al. 1978) and the results of these investigations provide useful data
which can be directly compared to and contrasted with the results of more
limited studies employing human cells and tissues. Therefore, separate
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(ENDOPLASMIC
RETICULUM)
BaP-O-SG
(DETOXIFICATION
PRODUCTS)
GLUTATHIONE
TRANSFERASE
(CYTOSOL)
CYTOCHROME P-450
MIXED-FUNCTION OXIDASE (MFO)
MFO
BaP OXIDES
EPOXIDE
HYDRASE
(ENDOPLASMIC
RETICULUM)
-•> BaP PHENOLS
MFO
MFO
BaP DIOL EPOXIDES
(PROPOSED ULTIMATE
CARCINOGENS)
BaP QUINONES
BaP DIHYDRODIOLS (PROPOSED PROXIMATE CARCINOGENS)
UDP-GLUCURONOSYL TRANSFERASE
(ENDOPLASMIC RETICULUM)
H2O-SOLUBLE CONJUGATES
(DETOXIFICATION PRODUCTS)
Figure III-l. Enzymatic pathways Involved 1n the activation and
detoxification of B[a]P (U.S. EPA 1979).
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metabolism in general, and B[a]P metabolism in particular, in both animals and
man.
The metabolites of POM produced by microsomal enzymes in mammals can
arbitrarily be divided into two groups on the basis of solubility. In one
group are those metabolites that can be extracted from an aqueous incubation
mixture by an organic solvent. This group consists of ring-hydroxylated
products such as phenols and dihydrodiols (Selkirk et al. 1974, Sims 1970),
and hydroxymethyl derivatives of those POM having methyl groups, such as
7,12-dimethylbenz(a)anthracene (DMBA) (Boyland and Sims 1967) and
3-methylcholanthrene (3-MC) (Stoming et al. 1977, Thakker et al. 1978). In
addition to the hydroxylated metabolites, are quinones produced by oxidation
of phenols. Labile metabolic intermediates, such as epoxides, can also be
found in this fraction (Selkirk et al. 1971, Sims and Grover 1974, Selkirk et
al. 1975, Yang et al. 1978).
In the second group of POM metabolites are the water soluble products
remaining after extraction with an organic solvent. Many of these derivatives
are formed by reaction (conjugation) of hydroxylated POM metabolites with
glutathione, glucuronic acid, and sulfate. Enzyme systems involved in the
formation of water-soluble metabolites include glutathione S-transferase,
UDP-glucuronosyl transferase, and sulfotransferases (Bend et al. 1976, Jerina
and Daly 1974, Sims and Grover 1974). Conjugation reactions are believed to
represent detoxification mechanisms only, although this group of derivatives
has not been rigorously studied.
The metabolite profile of B[a]P, which has recently been expanded and
clarified by the use of high pressure liquid chromatography (HPLC), is
depicted in Figure III-2. This composite diagrams shows three groups of
positional isomers, three dihydrodiols, three quinones, and several phenols.
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BENZO(o)PYRENE
/I
6-OH-Me
7-OH
[9,IO-diol-7,8-epox]
[7,8,9,10-tetroj]
4,5-dio
"9,lO-epox
[7,8-diol-9,K)-epoi]
[7,8,9,10-tetnrf]
CONJUGATES
BOUND MACROMOLECULES
DNA
RNA
PROTEIN
Figure II1-2. Metabolites of benzo[a]pyrene (U.S. EPA 1979)
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The major B[a]P metabolites found in microsomal incubations are
3-hydroxy-B[a]P, l-hydroxy-B[a]P, and 9-hydroxy-B[a]P. The B[a]P-4,5-epoxide
has been isolated and identified as a precursor of the B[a]P-4,5-dihydrodiol.
Other studies indicate that epoxides are the precursors of the 7,8-dihydrodiol
and 9,10-dihydrodiol as well. Considerable evidence has recently become
available which implicates the stereospecific form of 7,8-dihydrodihydroxy-
9,10-epoxy-B[a]P as an ultimate carcinogen derived from B[a]P (Jerina et al.
1976; Kapitulnik et al. 1977, 1978a, b; Levin et al. 1976; Yang et al. 1978).
Since the resonance properties of POM make ring openings difficult,
enzymatic attack in the microsomes functions to open double bonds and add an
oxygen-containing moiety, such as a hydroxyl group, to give it more solubility
in aqueous media (e.g., urine) and thus facilitate removal from the body. In
the formation of metabolic intermediates by oxidation mechanisms, relatively
stable POM are converted to reactive metabolites (i.e., epoxides). Thus,
nucleophilic attack of this reactive intermediate, through the formation of a
transient carbonium ion, would be greatly enhanced. Arylations of this type
are common to many classes of carcinogenic aromatic hydrocarbons. Therefore,
the microsomal cytochrome P-450-containing MFO system and epoxide hydrase play
a critical role in both the metabolic activation and detoxification of many
constituents of POM.
Various forms of liver microsomal cytochrome P-450 can be isolated from
animals treated with different enzyme inducers (Wiebel et al. 1973, Nebert and
Felton 1976, Conney et al. 1977, Lu et al. 1978). Moreover, the metabolite
profiles of B[a]P can be qualitatively altered depending on the type of
cytochrome P-450 present in the incubation mixture (Wiebel et al. 1975). This
observation has important implications in considering the carcinogenic action
of certain POM toward tissues from animals of different species, sex, age,
17
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nutritional status, and exposure to enzyme-inducing chemicals. Limited
evidence is also available indicating that multiple forms of epoxide hydrase
exist among animal species, which may also influence the pattern of POM
metabolism with respect to carcinogenic bioactivation (Lu et al. 1978).
An important consideration in evaluating the health hazards of POM is
whether metabolism in various animals tissues and species is indicative of the
pattern of POM metabolism in the target organs of humans. Moreover, it is
essential to determine whether differences occur in the metabolism of POM by:
(a) different tissues in the same animal; and (b) different animals of the
same species.
Numerous studies have shown that quantitative differences exist in the
metabolism of B[a]P by different tissues and animals species (Sims 1976, Leber
et al. 1976, Wang et al. 1976, Pelkonen 1976, Kimura et al. 1977, Selkirk et
al. 1976). For the most part, however, interspecies extrapolation of
qualitative patterns of POM metabolism appears to be a valid practice. On the
other hand, marked differences in patterns of tissue-specific metabolism may
prevent the reliable extrapolation of data from hepatic to extrahepatic (i.e.,
target organ) tissues. These differences may also exist in human tissues
(Conney et al. 1976).
Freudenthal and coworkers (1978) examined the metabolism of B[a]P by lung
microsomes isolated from the rat, rhesus monkey, and man. Their results
confirmed previous observations regarding the existence of considerable
species and intraspecies variation in B[a]P metabolism among samples from the
same species. In addition, it was apparent that qualitative and quantitative
interspecies variation also existed (Table III-l). Nevertheless, the
qualitative differences between man and other animal species were by no means
dramatic, and probably do not compromise the validity of extrapolations
18
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TABLE III-l.
METABOLITE PERCENTAGES OF B[a]P METABOLITES FROM RATS,
RHESUS, AND HUMAN LUNG MICROSOMAL ASSAYS
(Freudenthal et al. 1978)
Metabolite Percentages
(pmoles metabolite/pmoles total metabolites x 100)
Rat*
Rhesus t
Man t§
Metabolite
Pre-9,10
9,10-Diol
A
U1
4,5-Dlol
7,8-D1ol
1,6-01 one
3,6-D1one
6,12-Dione
9-OH
3-OH
1
9.7
4.4
8.3
5.3
4.4
7.8
6.8
12.6
40.8
2
6.3
3.4
9.2
5.2
7.5
8.0
8.6
11.5
40.2
3
9.6
2.9
8.3
8.0
8.3
9.9
8.6
3.5
41.1
1
2.7
1.5
6.9
9.0
4.2
11.4
14.5
11.8
7.3
30.8
2
3.0
4.6
9.2
8.6
14.8
16.0
8.0
35.9
3
5.3
2.6
7.7
7.7
5.1
12.8
20.5
15.3
23.1
1
8.9
4.1
24.9
22.5
22.5
' 5.7
11.4
2
7.1
3.9
15.0
11.6
13.8
18.3
6.2
24.0
3
6.0
7.5
13.3
12.6
19.2
27.4
13.9
4
30.0
9.9
4.4
8.5
15.7
8.5
22.9
*Lungs of five rats pooled for each group.
tDetermlnations made on lung samples from separate individuals.
SWith the exception of subject 4, activity determinations were made using microsomes which had been stored at
- 84°C.
IThe structural characteristics of unknown, U, may differ between species.
19
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concerning POM metabolism.
Patterns of B[a]P metabolism in human lymphocytes and human liver
microsomes are similar (Booth et al. 1974, Selkirk et al. 1975). However, in
cultured human bronchus (24 hours) and pulmonary alveolar macrophages, an
absence of phenols (i.e., 3-hydroxy-B[a]P) and paucity of quinones were
observed (Autrup et al. 1978). Instead, a relative abundance of the
trans-7,8-diol metabolite of B[a]P was demonstrated. This result is
noteworthy in light of the possibility that the 7,8-diol is capable of further
oxidative metabolism to an ultimate carcinogenic form of B[a]P. It is not
known whether a longer incubation period would have changed the pattern of
metabolite formation.
In summary, metabolism of constituents of POM is very complex although it
is catalyzed by the enzyme systems involved in the metabolism of B[a]P and
produces transient epoxide metabolites which, as a group, are known to be
carcinogenic. Although interspecies and intraspecies variations exist in the
metabolic profiles of aromatic hydrocarbons, there is evidence that
similarities in the qualitative patterns of metabolism of these compounds
among species allow interspecies extrapolations for the purpose of hazard
assessment and risk estimation.
Several generalizations seem applicable to most unsubstituted polycyclic
hydrocarbons, including the polynuclear aza-heterocyclic compounds identified
in Table II-l (U.S. EPA 1980a). Metabolic transformation may occur at
saturated carbon atoms to form in sequence, alcohols, ketones, aldehydes, and
carboxylic acids. More commonly, metabolic conversion at one or more aromatic
double bonds (K-region and non-K-region) leads to formation of phenols or
isomeric dihydrodiols through epoxide intermediates. Dihydrodiols can be
further metabolized to diol epoxides. Active intermediates are removed by
conjugation with glutathione or glucurom'c acid or by further metabolism to
20
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tetrahydrotetrols. Glutathione conjugates can be excreted In urine as
mercapturic acid.
Jerina et al. (1977, 1980) have supported the "bay region" theory which
proposes that diol epoxides can impart high biological activity when located
on angular benzene rings of polycyclic (polynuclear) aromatic hydrocarbons
and, furthermore, that the epoxide group forms part of the bay region in
carcinogenic compounds of this class. The hindered region between the 10 and
11 positions in the benzo[a]pyrene molecule is an example of a bay region.
Experimental data presented by Jerina et al. (1977, 1980) show that predicted
chemical reactivity for positional isomers of benzene ring diol epoxides of
specific polycyclic (polynuclear) aromatic compounds commonly correspond to
their demonstrated mutagenic and tumorigenic activities. For example, Jerina
et al. (1977) presented results from mutagenicity tests with Salmonella
typhimurium TA 100 on diol epoxides derived from non-K-region dihydrodiols of
benzo[a]anthracene to indicate a substantially greater mutagenic effect with
benzo[a]anthracene 3,4-diol-l,2-epoxides (isomer 1 and 2) compared to
corresponding 8,9-diol-10,ll-epoxide isomers and 10,ll-diol-8,9-epoxide
isomers. Hence, it appears that, in aromatic hydrocarbons containing four or
more benzene rings, the metabolic transformation of polycyclic (polynuclear)
aromatic hydrocarbons to their ultimate carcinogenic (dihydrodihydroxyepoxy)
forms is explainable by the bay region concept.
It should be noted that, according to Santodonato and Howard (1981), the
metabolism of polynuclear aza-heterocyclic compounds per se largely remains to
be investigated; therefore, the above generalizations on the metabolism of
this class of compounds are mainly inferred from known metabolic
characteristics of their homocyclic analogs, the polynuclear aromatic
hydrocarbons.
21
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AROMATIC AMINES
A general discussion on the metabolism of aromatic amines, which include
a- and B-naphthylamines, is presented in a National Research Council (1981)
assessment document on aromatic amines and is summarized herein. Aromatic
amines are primarily metabolized by oxidation, and oxidation at the nitrogen
atom or at carbon atoms in the aromatic ring may occur. Oxidation of primary
amines may occur according to the following scheme:
H
-NH2 s s -NOH v N -N = 0 v N02
amine hydroxylamine nitroso nitro
Little evidence is available to indicate that aromatic amines are oxidized
to nitro compounds. Secondary and tertiary amines are also oxidized at the
nitrogen atom. Dealkylation of tertiary to secondary amines may occur, and
hydroxylamines may be formed from partial N-dealkylation of secondary amines.
Hydroxylation of the aromatic ring results from activation of the free
amine group in aromatic amines. Primary hydroxylation occurs at the three
position of 1-naphthylamine and the one position of 2-naphthylamine.
Transformation of aromatic amines to metabolites that can react with
cellular macromolecules can occur by an initial oxidation at the nitrogen atom
followed by a second activation.
Probably the main detoxification route is conjugation of the hydroxyl
groups of metabolites of aromatic amines with glucuronic acid. Aromatic
amines can also be conjugated with sulfate, and primary amines can be
acetylated by several animal species.
22
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OTHER AROMATIC COMPOUNDS
Benzene metabolism is summarized in a U.S. EPA (1980b) water quality
criteria document. Benzene is metabolized to phenol as well as catechol and
hydroquinone. The major hydroxylation product is phenol, most of which is
found in urine conjugated with ethereal sulfate or glucuronic acid.
Phenylmercapturic acid and muconic acid also have been found as urinary
metabolites. The formation of phenol through an epoxide intermediate of
benzene has been proposed. Additional metabolic transformations for the
proposed epoxide intermediate of benzene include hydration and subsequent
oxidation to form catechol and conjugation to form premercapturic acid.
Hydroquinone production from mixed-function oxidase activity on phenol is also
possible. In humans, conjugation of phenol has been found to occur largely
with sulfate at low levels of benzene exposure and increasingly with
glucuronide with increasing benzene exposure.
The metabolism of phenol is summarized in a U.S. EPA (1980c) water quality
criteria document. Phenol is almost completely metabolized in humans with the
four main metabolites as sulfate and glucuronide conjugates of phenol and
hydroquinone. In rabbits, most phenol is oxidized to carbon dioxide and water
plus traces of 1,2-dihydroxybenzene and 1,4-dihydroxybenzene or is excreted in
urine as free or conjugated phenol.
As described in a Carcinogen Assessment Group (1980a) draft report on
toluene, the major pathway for toluene metabolism involves oxidation of the
methyl group to benzyl alcohol with further oxidation to benzaldehyde and
benzoic acid. Benzoic acid is mainly conjugated with glycine in the liver to
form hippuric acid. Small amounts of toluene may be converted to phenols
(4-cresol, 2-cresol) via an epoxide intermediate.
Xylene metabolism is described in a U.S. EPA (1980d) hazard profile on
23
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xylene. Xylene isomers (m-. o-, p-) can be oxidized to the corresponding
methyl benzoic acid which is conjugated with glycine or glucuronic acid.
Xylene isomers can also undergo ring hydroxylation to corresponding xylenols
(dimethylphenols) which can also be conjugated to form glucuronides or
ethereal sulfates. Methyl hippuric acid, a glycine conjugate of methyl
benzoic acid, has been found as the main urinary metabolite in experiments on
m- and p- xylenes. Paratolualdehyde has been identified as a metabolite of
p-xylene.
TRACE ELEMENTS
Metabolic transformation generally does not appear to serve a major role
in toxification/detoxification of the trace elements (metals) identified in
Table II-l. Discussion of this issue is summarized from U.S. EPA (1980e-j)
water quality criteria documents on the specific elements and from Venugopal
and Luckey (1978).
Pentavalent and trivalent arsenic is metabolically transformed mainly to
dimethylarsinic acid. Methylation of inorganic arsenic can serve as a
detoxification mechanism. The nature of the conversion of the pentavalent
form to the trivalent form, which can occur in vivo, remains unclear.
Trivalent arsenic can readily bind to tissue macromolecules at, for example,
sulfhydryl and hydroxyl groups, whereas pentavalent arsenic is less readily
bound (U.S. EPA 1980e).
Beryllium can bind to inhibit several enzymes and it can be concentrated
in cell nuclei. The bulk of circulating beryllium is in the form of colloidal
phosphate probably absorbed on plasma ex-globulin. Relatively minor amounts of
beryllium can be combined in a diffusible form with organic acids such as
citrate or phosphate (U.S EPA 1980f).
24
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Circulating chromium is mainly bound in a nondiffusible form with
proteins. At low levels, trivalent chromium is mainly bound to the
iron-binding protein, siderophilin. Chromium can presumably penetrate cells
in a hexavalent state and subsequently react with cell components.
Tetravalent chromium is reduced to trivalent chromium in cells. The chemical
form of chromium influences its pattern of biodistribution (U.S. EPA 1980g).
Cadmium has no known function in metabolism. It can be bound to
metal!othionein protein, especially in erythrocytes, liver, and kidney.
Cadmium in plasma is bound to high-molecular-weight proteins (U.S. EPA 1980h).
Cobalt can be retained in several tissues. Cobalt stored in intestinal
mucosa can be lost through epithelial desquamation. Cobalt can be eliminated
from the body as a cobalt-histamine complex (Venugopal and Luckey 1978).
Orally administered iron is absorbed across the gastrointestinal mucosal
epithelium by a mediated transfer mechanism. Most circulating iron is bound
to transferrin. Iron is primarily stored as ferritin or hemosiderin in liver,
bone marrow, and spleen (Venugopal and Luckey 1978).
Lead is mainly deposited in bone and smaller amounts are stored in soft
tissues (Venugopal and Luckey 1978).
Nickel is stored in body tissues and can be bound to metalloprotein (U.S.
EPA 1980i).
Little is known about selenium biochemistry in mammalian systems. At
nutritional levels selenium is incorporated into specific functional proteins;
at higher levels selenium can bind to molecules normally combined with sulfur.
The main urinary metabolite of selenium is trimethylselenium ion. Inorganic
selenium usually does not combine with amino acids (U.S. EPA 1980J). Selenium
can also function as an inhibitor of tumor induction by chemical carcinogens.
25
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OTHER GASES
Ammonia can be converted to urea in the liver. Ammonia is also formed
endogenously by deamination of ami no acids and amides and by bacterial
conversion of urea in the gut (U.S. EPA 1980k).
Carbon disulfide is lipid soluble and binds to proteins. It can react
reversibly with amino acids to yield thiocarbamates. Sulfur released during
desulfuration of carbon disulfide can form covalent bonds with other sulfur
radicals. Carbon disulfide metabolites in human urine include mainly thiourea
and also mercaptothiazolinone and possibly 2-mercapto-thiazoline-4-carbamic
acid. It can be desulfurated in the liver to form carbonyl sulfide which is
further oxidized to form C02. Bivalent sulfur can also be formed which is
oxidized to sulfate (World Health Organization 1979).
Carbon monoxide combines with hemoglobin to form carboxyhemoglobin, and it
can also reversibly bind with cellular heme groups (U.Si. EPA 19801).
The main metabolic pathway for hydrogen cyanide is conversion to
thiocyanate via rhodanase. Minor pathways include conjugation of cyanide with
cysteine to form 2-iminothiazolidene-4-carboxylic acid, binding of cyanide
with hydroxocobalamin, and excretion of unchanged hydrogen cyanide through the
lungs. Cyanide can also be converted to formate and carbon dioxide (U.S. EPA
1980m).
Hydrogen sulfide can be detoxified by oxidation to inorganic sulfur on
interaction with oxyhemoglobin. Sulfide ions can be oxidized to sulfate or
thiosulfate ions (Roy and Trudinger 1970).
The nature of absorption and biodistribution of nitric oxide is presently
unknown; however, nitric oxide can react with hemoglobin to form methemoglobin
and nitrosylhemoglobin (Goldstein et al. 1980). Nitric acid is known to react
in vivo with amines to yield N-nitrosamines, many of which are known animal
carcinogens (Magee et al. 1976).
26
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IV. MUTAGENICITY* AND CELL TRANSFORMATION
The objective of this mutagenicity evaluation is to determine whether or
not coke oven emissions have the potential to cause somatic mutations in
humans. This evaluation is a qualitative assessment based on two kinds of
available information: (1) data concerning the mutagenic potential of the
complex mixture of coke oven door emissions and the complex mixture from the
coke oven collecting main, and (2) data concerning the mutagenic potential of
the individual components that have been identified in coke oven emissions.
To briefly summarize the findings, the complex mixture of organics extracted
from coke oven door emissions was detected as mutagenic in bacteria. The
solvent-extracted organics of the material sampled from the coke oven
collecting main caused mutations in bacteria and mammalian cells in culture.
Chemical analysis of coke oven emissions has revealed the presence of several
components (e.g., certain polynuclear aromatic hydrocarbons, aza-heterocyclic
compounds, aromatic amines, etc.) known to be genotoxic when evaluated
individually in various mutagenicity tests. In addition, there are studies
that show that air particulates collected topside of coke oven batteries are
mutagenic in bacteria and mammalian cells in vitro. The available data
concerning the mutagenicity of coke oven emissions and air particulates
collected topside of coke ovens are discussed below.
STUDIES EVALUATING SOLVENT-EXTRACTABLE ORGANICS OF COKE OVEN DOOR EMISSIONS
Data concerning the potential mutagenic hazard of coke oven emissions is
limited to one bacterial study sponsored by the U.S. Environmental Protection
Agency's Office of Research and Development (U.S. EPA 1977b). In this study,
a sealed hood was fitted over the door of a coke oven, and emissions leaking
*Prepared by the Reproductive Effects Assessment Group.
27
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from the coke oven door were collected during an approximately 13-hour coking
cycle. Particulate emissions were collected on the filter of a high volume
sampler and volatile organics were collected on a Tenax-GC adsorbent column.
Several samples were collected representing different time segments of the
coking cycle (as shown below). Samples collected later in the coking cycle
represent longer time segments because emissions from the doors decreased as
time increased into the coking cycle.
Sample Extracts Length of Sampling Segments
Absorbent Filter
Al A1F 1 (represents the first hour of the coking cycle)
A3 A3F 2 (represents the beginning of the third hour up
to the fifth hour)
A5 A5F 5 (represents the beginning of the ninth hour
through the thirteenth hour)
A6 — -- compressor air supply (blank)
The adsorbent column samples were soxhlet-extracted with the nonpolar
solvent pentane for 24 hours and the filter samples were soxhlet-extracted
sequentially with the more polar solvents methylene chloride and methanol
(approximately 3 days). The seven sample extracts were evaluated at seven
concentrations ranging from 5 ul to 10.0 ul of sample (in 50 ul of DMSO) in
the Salmonel1 a/mammalian microsome plate incorporation assay using the
standard tester strains TA 100, TA 98, TA 1535, TA 1537, and TA 1538.
Positive responses 1n TA 98 were observed without S-9 mix for the filter
extract samples A1F, A3F, and A5F (see Figure IV-1 A). A weak positive
response (twofold increase) was observed in TA 1538 (minus S-9 mix) for the
filter extract A1F. The addition of S-9 mix (prepared from rat livers)
28
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450- A- - S9MDC
400 ..
350
I 250
200
150
100
A1F
A1F
A3F
ASF
2345
ul of «aiple (In 50 ul of EMSO)
4 5
ul of sanpla (in 50 ul of QBO)
Figure IV-1 A, B. The mutagenic activity of coke oven door emissions (A, In the absence of metabolic
activation; B, In the presence of metabolic activation). Emissions were collected over an
approximately 13-hour coking cycle and evaluated In the Salmonel1 a/mammal 1 an mlcrosome assay using
TA 98. Sample A1F represents the first hour of the coking cycle, sample ASF represents a 2-hour
segment from the beginning of the third hour up to the fifth hour of the coking cycle, and sample A5F
represents a 5-hour segment from the beginning of the ninth hour through the thirteenth hour of the
coking cycle (taken from U.S. EPA 1977b).
29
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greatly enhanced the mutagenic response for all filter extract samples in
strains TA 98, TA 100, TA 1538, and TA 1537. The filter extracts were not as
active in TA 100 as they were in the other tester strains. These responses
appeared as concentration-related increases in revertant colonies (see Figure
IV-1 B). "Toxic effects" were reported for sample A5F at 10 ul. A1F, A3F,
and A5F were not detected as mutagenic in the base-pair substitution sensitive
strain TA 1535 in the absence or presence of S-9 mix.
The adsorbent column extracts Al, A3, A5, and A6 (compressor air supply)
were evaluated for mutagenicity in the same manner as the filter extracts. No
mutagenic activity was detected in the absence of S-9 mix. In the presence of
S-9 mix, the absorbent column extracts Al and A3 were detected as weakly
mutagenic in frameshift-sensitive strains. Sample Al was detected as positive
in the frameshift-sensitive strain TA 1537, whereas in the other strains (TA
1538, TA 98, and TA 100), the responses were similar to the spontaneous
revertant counts, or the positive responses that were reported either appeared
as nonreproducible or not concentration-related. Sample A3 was detected as
weakly positive in strains TA 1537 and TA 1538, but was not detected as
mutagenic in strains TA 98 and TA 100. The mutagenicity of sample A5 was
inconclusive because the positive responses reported were not reproducible.
"Toxic effects" were reported for A5 at the high concentrations. The
absorbent extracts were not detected as positive in TA 1535 with or without
S-9 mix. The compressor air supply sample (A6) was not detected as positive
under any of the treatment conditions. It should be emphasized that volatile
components were collected on the absorbent column and that highly volatile
components may not be effectively detected as mutagenic unless precautions are
taken to prevent excessive evaporation and thus ensure exposure to the
indicator organisms. Such measures were not reported to have been taken for
30
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the absorbent extracts.
The above study of solvent-extracted organics of filter and absorbent
samples demonstrated that coke oven door emissions caused frameshift mutations
in bacteria. The mutagenic responses required or were enhanced by a mammalian
microsomal activation system. This finding is consistent with mutagenicity
studies of several individual components identified in the complex mixture as
frameshift-acting mutagens requiring metabolic activation. Information on the
mutagenicity of individual constitutents will be summarized later in this
section.
STUDIES EVALUATING THE COMPLEX MATERIAL FROM THE COKE OVEN COLLECTING MAIN
In addition to the study on coke oven door emissions, a related complex
material was sampled by EPA (Huisingh et al. 1979) from a coke oven collecting
main (where the coke oven gas resulting from carbonization cools and
condenses). This sample was collected from a separator collector located
between the gas collector main and the primary coolers within the coke oven
battery (Huisingh 1981, unpublished) at the same coke plant (located in
Gadsden, Alabama) used by Huisingh et al. (1979) to sample air particulates
topside of a coke oven battery referred to later. The coke oven main sample
was dissolved in DMSO to test in a variety of in vitro mutagenicity assays.
It should be noted that although this complex mixture is derived from coke
oven emissions condensate and contains similar components, it is still
qualitatively and quantitatively different in composition from coke oven
emissions.
31
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The coke oven main sample was tested twice in the Salmonella/microsome
plate incorporation assay on separate days using tester strains TA 1535, TA
100, TA 98, TA 1538, and TA 1537 (Claxton and Huisingh 1981, unpublished).
This coke oven condensate was not detected as mutagenic in the base-pair
substitution-sensitive strain TA 1535 in the absence of S-9 mix up to a
concentration of 500 ug/plate of test material (precipitate formed at this
concentration) or in the presence of S-9 mix (livers were prepared from
Aroclor-induced rats) up to a concentration of 100 ug/plate of test material.
The frameshift-sensitive strains TA 1537, TA 1538, and TA 98 gave marginal
responses in the absence of S-9 mix (twofold or less increase in revertant
colonies above the spontaneous values) at the highest concentrations examined.
However, these responses were interpreted as inconclusive because they did not
appear as reproducible or concentration-related. Strain TA 100, a base-pair
substitution-sensitive strain that is also sensitive to frameshift mutagens
(McCann et al. 1975), was weakly reverted (approximately twofold increase in
revertants above the solvent control counts) without metabolic activation in
two different trials. When S-9 mix was incorporated in the assay, the number
of revertant colonies per plate was greatly increased above the spontaneous
values for strains TA 100, TA 1538, and TA 98. These positive responses
appeared as concentration-related increases in revertant colonies and were
reproducible. Therefore, from these studies, it appears that the coke oven
main sample was primarily detected as indirect-acting in frameshift-sensitive
strains.
Mitchell (1981, unpublished) evaluated the ability of the coke oven main
sample to induce gene mutations in L5178Y mouse lymphoma cells with and
without a rat liver microsomal activation system (S-9 mix prepared from livers
of Aroclor-induced rats). The concentrations evaluated (in duplicate) in the
32
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absence of metabolic activation ranged from 0.5 tig/ml to 50 ug/ml in one
experiment, 30 ug/ml to 70 ug/ml in another, and 20 ug/ml to 150 ug/ml in a
third experiment. At 50 ug/ml, 70 ug/ml, and 150 ug/ml, total relative
growths* of 70%, 61%, and 21%, respectively, were reported. Concentrations
above 70 ug/ml were reported to form a precipitate. Concentrations ranging
from 0.5 ug/ml to 70 ug/ml did not increase the frequency of mutant colonies
over that of the solvent control by more than twofold. In an assay in which
the test material was evaluated up to 150 ug/ml, a fourfold increase in mutant
colonies over the solvent control frequency was reported at 150 ug/ml.
However, precipitates in samples from concentrations of 60 ug/ml to 150 ug/ml
were reported to be "overlooked" by the investigators during the exposure and
wash steps and not noticed until later. Because these precipitates may have
been present during the expression and selection periods of the test, the
interpretation of the dose-dependent response is difficult. Thus, based on
these data, it is inconclusive whether or not the test sample was mutagenic in
the absence of S-9 activation. In the presence of metabolic activation,
however, the test material was mutagenic in two separate trials. Because the
test material was more cytotoxic in the presence of metabolic activation than
in its absence, the retesting of the material for its ability to induce mutant
colonies was conducted over a narrow range of concentrations (0.5 ug/ml to 10
ug/ml). At concentrations (5 ug/ml, 6 ug/ml, and 8 ug/ml) that did not
appreciably reduce total relative growth less than 30%, approximately twofold
to threefold increases in mutant colonies above the spontaneous frequencies
(solvent control) were reported.
The genetic effects of the coke oven main sample were also determined in a
*Percentage of relative total growth = (relative suspension growth/relative
cloning efficiency) x 100.
33
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Saccharomyces cerevisiae D3 preincubation assay for mitotic recombination
(Mortelmans et al. 1980, unpublished). Prior to plating in agar, yeast cells
were preincubated with the test material at a concentration range of 50
ug/plate to 5,000 ug/plate for 2 hours in the absence or presence of S-9 mix.
When tested twice under the above conditions, recombinogenic activity did not
differ from the solvent control and no toxic effects were reported. It should
be noted that the known mutagens benzo[a]pyrene and 2-nitrofluorene were also
detected as negative in this assay. The concurrent positive control
1,2,3,4-diepoxybutane, a direct-acting mutagen, greatly enhanced
recombinogenic frequency, thus indicating the system was working properly
without S-9 activation. Therefore, these negative results are most likely a
reflection of the sensitivity of the assay.
Even though the coke oven collecting main sample is not a true
representative sample of coke oven emissions, it does contain similar
components that may be emitted. Thus, the mutagenic responses observed in
bacteria and in mammalian cells in culture are considered as supportive
evidence for the mutagenicity of coke oven emissions.
STUDIES EVALUATING SOLVENT-EXTRACTABLE ORGANICS OF AIR PARTICULATES COLLECTED
ON TOP OF COKE OVENS
Although these are not studies of "pure" coke oven emissions per se, two
reports discussed below have bearing on the mutagenicity of coke oven
emissions. These studies show that air particulate samples collected topside
of coke ovens are mutagenic in in vitro bioassays.
In a study conducted in Japan, the relative mutagenic activity was
concurrently determined for air particulates from a coke mill and other
industrial areas and for ambient air particulates from various residential
areas (Tokiwa et al. 1977). Air particulates were collected on glass fiber
34
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filters for 24 hours or 48 hours from six different locations in industrial
areas of Ohmuta City and from six different locations in residential areas of
Fukuoka City using a high air-volume sampler.*
A high air-volume sampler would collect all particle sizes, i.e.,
respirable (< 1.7 urn in diameter), nonrespirable (> 5 urn), and noninhalable
(> 15 urn). Information concerning sample collection (e.g., wind-direction
during sampling) was not provided in the report. Although the position of the
samplers also was not described in the report, Tokiwa (1981, unpublished)
indicated in a letter to the Reproductive Effects Assessment Group (REAG)t
that the sampler at the coke mill (sample 123) was located on top of a coke
oven for 48 hours. For the other industrial samples, Tokiwa only indicated
that collection points were around "several factory [sic] in the city." The
residential samples were collected in heavily trafficked areas. The organics
bound to the air particulates were soxhlet-extracted with methanol for 8
hours. Because methanol is a polar solvent, it will preferentially extract
more polar types of organics from the air particles. It should be noted that
Jungers et al. (1980) have found methanol to be less effective at extracting
mutagens from air particulates than dichloromethane (the solvent used in a
study by Huisingh et al. 1979, which is discussed later). The methanol
extracts were evaporated to dryness and dissolved in DMSO for mutagenicity
testing in the Salmonella/microsome assay using tester strains TA 1535, TA
1536, TA 1537, TA 1538, TA 100, and TA 98 with and without a mammalian
activation system (S-9 mix prepared from livers of Aroclor-induced rats). The
authors stated in the report that in the absence or presence of S-9 mix, the
*0hmuta and Fukuoka are within approximately 80 miles of each other.
tA written request was made to Tokiwa to secure information concerning the
location of the samplers.
35
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solvent-extracted orgam'cs of air particulates collected topside of a coke
oven were not detected as mutagenic in the base-pair substitution-sensitive
strains TA 1535 and the frameshift-sensitive strain TA 1536, but were
mutagenic for the frameshift-sensitive strains TA 1537, TA 1538, TA 98, and
the base-pair substitution-sensitive strain TA 100, which is also sensitive to
certain frameshift-acting mutagens. The data generated in the presence of S-9
mix are illustrated in Figure IV-2. The extracted orgam'cs were most active
in strain TA 98. Although the authors indicate in the report that the topside
coke oven sample was evaluated without S-9 mix, they do not report the
results. Towika (1981, unpublished) indicated that the positive responses
observed in the absence of S-9 activation "was very low." Thus, it appears
that the mutagenicity of this complex mixture was primarily detected as
indirect-acting. Chemical analysis (GC/MS analysis) of the topside coke oven
sample revealed the presence of several polycyclic aromatic hydrocarbons known
to be frameshift-acting mutagens requiring metabolic activation (e.g.,
chrysene, dibenzoanthracenes, benzoanthracenes, benzopyrenes,
benzofluoranthenes).
In the report by Tokiwa et al. (1977), it was found that air particulates
from industrial areas, particularly those collected topside of a coke oven,
were more mutagenic than air particulates from residential environments. As
shown in Table IV-1, the mutagenic activity in strain TA 98 (in the presence
of S-9 mix) of air particulates collected topside of a coke oven In Ohmuta and
other industrial sources is compared with the mutagenic activity of ambient
air particulates from residential areas.* This comparison was based on data
expressed as revertants per cubic meter (m3) of air. The authors do not
*It should be noted that the mutagenic activity of ambient air may vary
over time and with weather conditions.
36
-------
700 -_
TA 98
100 --
400
600 800
ug per plate
1000
Figure IV-2. Mutagem'c activity of methanol extracts of air participates
collected topside of a coke oven. The extracted sample was evaporated and
diluted in DMSO for evaluation in the Salmonella/mammalian microsome assay
in the presence of S-9 mix (taken from Tokiwa et al. 1977).
37
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TABLE IV-1. SUMMARY OF THE MUTAGENIC ACTIVITY IN SALMONELLA TYPHIMURIUM
OF ORGANICS EXTRACTED FROM AIR PART1CULATES COLLECTLU
IN INDUSTRIAL AND RESIDENTIAL AREAS OF JAPAN*
Sample Number
Industrial Areast
123 (coke mill)
160
161
162
163
164
Residential AreasS
86
152
21
150
64
126
Revertants per m3 air
445.0
288.0
94.0
22.2
138.0
103.0
12.4
77.6
12.3
52.4
13.2
7.1
*Samples were collected in the industrial areas of Ohmuta and residential
areas of Fukuoka. The mutagenicity of samples was evaluated with Salmonella
typhimurium TA 98 in the presence of S-9 mix (taken from Towika et al. 1977).
tSample numbers 161, 163, and 164 were not identified except as
industrial areas. Sample 160 was identified as ambient air collected in the
middle of factory districts. Sample 162 was identified as a sample collected
far from the factory districts.
SSamples were identified only as residential areas at heavily trafficked
locations.
38
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discuss how the values for revertants/m3 were derived. It appears from the
report that the number of revertants per m3 of air was determined only from
the highest concentrations tested for each sample and that the mutagem'c
activities were not expressed as the slope of the dose-response curves (i.e.,
number of revertants per ug increase in concentration). Determination of the
slopes of the dose-response curve provides a better reflection of the
mutagem'c potency rather than simple selection of one dose point from the
dose-response curve. However, from examination of the dose-response curves
illustrated in the report and reproduced in Figure IV-3, all of the samples
from residential areas and the topside coke oven sample (123) caused linear
dose-responses in strain TA 98. Thus, the mutagem'c activity (i.e.,
revertants/m3) determined from the highest concentration tested should be
very similar to the mutagem'c activity expressed as the slope of the linear
dose-response curve. However, because some of the industrial samples follow a
nonlinear response* at the high concentrations tested, regression analyses are
necessary to determine if the topside coke oven sample is significantly
different than some of the other industrial sources. Therefore, this study
shows that, the mutagem'c activity (expressed as revertants per m3 of air)t
of solvent-extracted organics of air particulates collected topside of a coke
oven is 6- to 63-fold higher than the mutagem'c activity of organics extracted
from ambient air collected at trafficked locations in residential areas.
Air particulates also have been collected topside of a coke oven battery
*0ne major problem with evaluating complex environmental mixtures in the
Ames test (or other short-term tests) is high toxicity. Many times the
dose-response follows a nonlinear pattern at higher concentrations (Stead et
al. 1981).
tThe topside coke oven sample also appeared more mutagem'c than
residential samples (but not for the other industrial sources) when the data
were expressed as revertants/ug.
39
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1500
1000
| 500
a.
ti
ex.
•3 1000
3 500 ..
200
100
fit MO*
TAISM
Vg per plate
Figure IY-3. The dose-response curves from the Salmonella/mammalian mlcrosome assay of each sample
collected In Industrial areas of Ohmuta (A) and in residential areas of Fukuoka (B). Sample 123
represents air partlculates collected topside of a coke oven. The spontaneous revertant counts have
been subtracted (taken from Towlka et al. 1977).
40
-------
located in Gadsden, Alabama (Huisingh et al. 1979). Huisingh (1981,
unpublished) described this coke oven battery as "a newer generation of coke
ovens designed to reduce fugative coke oven emissions." Air particulates
(size < 1.7 urn) were collected for approximately 2100 hours on electrostatic
precipitator plates of two massive air volume samplers (collection rate 17.3
m-Vmin each) positioned side by side at one end of a coke oven battery. The
organics bound to the particulate matter were soxhlet-extracted with
dichloromethane (DCM) and tested for their mutagenic potential in several j_n_
vitro bioassays by different investigators. This topside coke oven sample was
found to cause point mutations in Salmonella typhimurium and gene mutations,
sister chromatid exchange formation, and DMA strand breaks in mammalian cells
in culture. These results are briefly described below.
Concentration-related increases in revertant counts were reported with the
frameshift-sensitive strain TA 98 when the topside coke oven extract was
tested at 25, 75, 125, 250, 750, and 1250 ug/plate (Claxton 1979 and
unpublished data). A positive response was also reported for strain TA 100.
The addition of S-9 mix (prepared from livers of Aroclor-induced rats)
slightly increased the mutagenic response (an approximately twofold increase
in revertant colonies above those induced in the absence of S-9 mix) in TA 98
but not in TA 100. Negative results were reported for the base-pair
substitution-sensitive strain TA 1535 in either the presence or absence of S-9
mix.
Mitchell et al. (1979) examined the ability of the topside coke oven
extract to cause gene mutations using L5178Y mouse lymphoma cells. Following
a fixed treatment time (4 hours), a concentration-related increase in
trifluorothymidine-resistant colonies was observed in three separate trials
in the absence of in vitro metabolic activation. For example, at
41
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concentrations that did not reduce the relative total growth* below 40% (50
ug/ml to 100 ug/ml), induced mutant frequencies up to approximately three
times the spontaneous mutant frequencies were reported. The addition of S-9
Aroclor-induced rat liver enzyme activation caused an increase in
cytotoxicity. Based on the results of a single experiment conducted at
concentrations up to 25 ug/ml, the addition of S-9 metabolic activation
appeared to enhance the response in a concentration-dependent manner; for
example, at 17.5 ug/ml (45% relative total growth), a fourfold increase in
mutant colonies above the spontaneous values was observed.
In a second gene mutation assay using mammalian cells in culture, Curren
et al. (1979) reported that several different concentrations of the topside
coke oven extract sample enhanced the frequency of ouabain-resistant colonies
above the spontaneous frequency in mouse BALB/c 3T3 cells in the absence of in
vitro metabolic activation; but for this response, there was no
concentration-dependent increase. In the presence of metabolic activation
(Aroclor-induced rat liver S-9 mix), an increase in the number of
ouabain-resistant clones was also reported. However, the authors indicated
that the spontaneous mutation frequency was significantly higher than the
historical values observed for that cell line, thus making interpretation of
the results difficult. Because of the problems described above and because
neither the toxicities nor mutation frequencies of the concentrations examined
were reported, the positive results of this study are considered questionable.
The ability of the topside coke oven extract to cause gene mutations in
mammalian cells was also evaluated by a third laboratory using the CHO/HGPRT
assay (Casto et al. 1979, 1980). Increases in variant colonies were only
observed at high cell killings. For example, at 200 ug/ml (82% cell killing)
'Percentage of relative total growth = (relative suspension growth/relative
cloning efficiency) x 100.
42
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a threefold increase in 6-thioguanine (6TG) resistant colonies above the
negative control was reported. It should be noted that concurrent positive
controls were not included in the study design. Also, S-9 liver enzyme
activation was not incorporated in the study design.
Mitchell et al. (1979) evaluated the ability of the coke oven sample to
cause sister chromatid exchange (SCE) formation in Chinese hamster ovary cells
with and without S-9 activation. The results of a single experiment indicated
that the coke oven sample caused an increase in DNA damage in a
concentration-dependent manner as measured by SCE formation. At the highest
concentrations tested, an approximately twofold increase in SCE formation
above the solvent control was reported for experiments in the presence and
absence of S-9 mix. The percentage of cell survival or effect on mitotic
induction of the concentrations tested (up to 250 ug/ml for 2 hours in the
presence of S-9 mix, and up to 31 ug/ml for 21.5 hours in the absence S-9 mix)
was not reported; however, the authors indicated that the highest
concentration yielded a sufficient number of M2 metaphases (i.e., cells that
had divided twice) for analysis. When Casto et al. (1979) treated a culture
of Syrian hamster embryo cells with 250 ug/ml or 125 ug/ml of the coke oven
extract for 18 hours in the absence of exogenous metabolic activation, DNA
strand breakage was detected as determined by sedimentation profiles in
alkaline sucrose gradients.
Mitchell et al. (1979) reported that, in the absence of S-9 mix,
recombinogenic activity in Saccnaromyces cerevisiae D3 was not detected after
a 4-hour fixed treatment time at concentrations of the coke sample ranging
from 10 ug/ml (100% survival) to 1000 ug/ml (61% survival) or when re-tested
at 100 ug/ml survival) to 1000 ug/ml (100% survival). Although a slight
43
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increase was observed in the presence of in vitro metabolic activation, the
results were not concentration-related or reproducible and thus are considered
negative.
In the Gadsden study it should be noted that the samplers were positioned
at the end of the coke oven battery with the prevailing wind direction upwind
from the coke oven (Kew 1981, Huisingh 1979). Thus, the 2100-hour sample
collected was diluted with ambient air. The exact extent of the dilution is
not known, but it is thought to be significant (Workshop on Diesel Engine
Exhaust 1981). Although dilution with ambient air occurred, chemical analysis
showed that the polynuclear aromatic hydrocarbon content is not typical of
ambient air (Huisingh 1981, Strup and Bjorseth 1979). (The sampler position
and wind conditions during collection are not available for the 48-hour sample
of the Ohmuta study.) Nevertheless, because the Gadsden sample was from a
single source and was apparently diluted significantly with ambient air
particulates, the mutagenic potency of this sample may not be representive of
air particulates found topside of "controlled" coke ovens. Also, the Gadsden
(and the Ohmuta) study did not involve a concurrent collection of samples from
a moderate distance upwind and downwind from the coke oven battery to enable a
determination of background mutagenic activity for the immediate vicinity.
Both the Ohmuta study by Towika et al. (1977) and the Gadsden study by
Huisingh et al. (1979) show that air particulates collected topside of coke
ovens are mutagenic in Salmonella. The Gadsden sample was also mutagenic in
mammalian cells in vitro. These studies have bearing on the mutagenicity of
coke oven emissions because the samples were collected on the top of coke
ovens. Although the mutagenic activity cannot be exclusively attributed to
coke oven emissions because of the ambient air contamination (particularly in
44
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the Gadsden study), these emissions are a likely source of mutagenic air
particulates. *"
In the aforementioned discussions on data concerning complex mixtures, it
should be cautioned that there are problems associated with using short-term
tests to ascertain the mutagenic potency of complex environmental mixtures
which are usually comprised of hundreds of components. For example, potential
mutagenic components present at low concentrations in the complex material may
not be detected because their activity is overridden by the high toxicity of
other components (Epler et al. 1979, 1980). Highly volatile components will
not be detected as mutagenic unless precautions are incorporated into the
study design to prevent excessive evaporation and thus ensure exposure of the
indicator organisms. Such measures were not reported to have been taken in
the studies mentioned above on coke oven-derived products and thus the results
may not reflect the magnitude of the mutagenic potential of these materials.
In addition, the organics screened for coke oven emissions were
solvent-extracted and only those organics extracted with those particular
solvents would have been evaluated for their mutagenic activity. Moreover,
the activation system employed (in the cases above, the S-9 fraction was
derived from livers of Aroclor-induced rats) may not effectively metabolize
some potential promutagen components in the mixture (Dent 1979, Rao et al.
1978). Based on these considerations, it must be stressed that the tests to
assess the mutagenicity of coke oven emissions, coke oven main sample, and air
particulates collected topside of coke ovens were conducted using standard
protocols and the concern is raised that the results obtained may
underestimate the actual mutagenic potential of the material.
45
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STUDIES EVALUATING URINE CONCENTRATES OF COKE PLANT WORKERS
Within a coke plant, coke oven battery workers have a high exposure to
coke oven emissions, which are comprised of known mutagens and are a source of
polycyclic organic matter. A method to demonstrate human exposure to mutagens
is bacterial mutagenicity testing of body fluids (e.g., urine, blood, feces).
In a study conducted by Holler and Dybing (1980), urine concentrates from
coke plant workers were evaluated for their mutagenic effects in the
Salmonella/mammalian microsome assay. Urine was collected before and after
work from 10 workers who smoked 10 to 20 cigarettes per day (workers rolled
their own cigarettes) and from 10 workers who did not smoke. The personal
exposure to polycyclic organic matter (POM) varied greatly among the workers
within each group (i.e., smokers versus nonsmokers). As shown below, three
job types were sampled: foremen, truck drivers, and coke oven battery workers.
Job Types
Smokers
Nonsmokers
coke oven battery workers
truck drivers
shift foreman
5
4
1
2
6
2
Within the job type "coke oven battery workers," there are different
levels of exposure to POM or coke oven emissions. However, this general class
(which includes larry car operators, door cleaners, push car operators, etc.)
would have a higher exposure to POM than would the other two job types, "truck
drivers" and "shift foreman." Ten nonplant workers who smoked and four
nonplant workers who were nonsmokers served as control groups. The chemicals
and/or their metabolites in urine samples were absorbed on a nonpolar resin
46
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column (XAD-2) and diluted with acetone. It should be noted that the
extraction and concentration methods can influence the ability to detect
mutagenic metabolites in the urine. After the urine samples were evaporated
to dryness, they were dissolved in DMSO for mutagenicity testing in the plate
incorporation assay using the Salmonella tester strains TA 100 and TA 98. The
authors stated that preliminary results showed that very little or no
mutagenic activity was detected with strain TA 100 (data not reported) and
thus they used strain TA 98 for further studies. The authors concluded that
the mutagenic activity of urine from POM-exposed nonsmokers was not
significantly different at the 95% level when compared to the mutagenic
activity of nonexposed nonsmokers or to the spontaneous revertant counts. It
is difficult to interpret these results because of the following deficiencies
in the reporting of the data or in the study design: (1) it is not clear from
the report if the authors' conclusions are based on experiments conducted in
the presence or absence of S-9 mix, (2) individual revertant counts (data are
illustrated in histogram) and positive control data are not reported, (3) it
appears that the authors tested only one concentration of urine instead of a
range of concentrations, (4) the authors used a Student's t-test to compare
the POM-exposed group to the nonexposed group and did not compare individuals
of a certain job type (i.e., exposure level) to the control population (The
authors refer to each test person by number and do not identify the job type
or exposure level of each number.), and (5) only two workers with high POM
exposure job types (coke oven battery workers) are included in this
nonsmoker-POM-exposed group.
The urine of the smoker-POM-exposed group was reported as mutagenic only
in the presence of S-9 mix (prepared from livers of Aroclor-induced rats). It
was reported that the addition of 6-glucuronidase (which hydrolyzes possible
47
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conjugates) to the urine concentrates did not enhance the mutagenic effects
observed in tester strain TA 98. The authors concluded that the ROM-exposed
smokers did not differ at the 95% level from nonexposed smokers. Again, the
authors are comparing one group with another and not individuals with certain
exposure levels to the control population. They do state in the report that a
suggestion of higher mutagenic activity of urine extracts was found when high
POM exposure workers were compared with lower POM exposure workers. However,
they indicated that a larger number of workers are needed to establish a
significant difference from the control population. The results of the study
by Moller and Dybing (1980) are considered inconclusive because of the
problems described above.
MUTAGENICITY OF INDIVIDUAL COMPONENTS IDENTIFIED IN COKE OVEN EMISSIONS
Several polycyclic components identified in coke oven emissions have been
shown to be potentially mutagenic in a variety of tests. It is not the intent
of this evaluation to provide an exhaustive survey of all the mutagenicity
tests that have been done with these components or with polycyclic organic
matter. References concerning the mutagenicity of polycyclic compounds can be
found in the Environmental Mutagen Information Center's Files, and reviews by
Brookes (1977), Bruce and Berry (1980), and Kimball and Munro (1981) summarize
much of this literature. Briefly, the mutagenicity of some of these
components is well-established, while the mutagenicity of others is
suggestive. In addition, of those components of the complex mixture known to
be mutagenic, the possibility exists that mutagenic chemical substances whose
activity has not been characterized may be present or that some constituents,
which may act as promoters or modifers of carcinogenesis, are present. Table
IV-2 is a selected list of organic components that have been reported positive
48
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TABLE IV-2. MUTAGENIC ACTIVITY IN SALMONELLA TYPHIMURIUM OF SELECTED ORGANICS
IDENTIFIED IN
Chemical S-9
Acenapthylene
Acridine
Anil ine
Anthracene
Benz[a]anthracene
Benzo[a]pyrene
Benzo[b]fluorene
Benzo[e]pyrene
Benzo[g,h,i]perylene
Carbazole
Coronene
Chrysene
Dibenz[a ,j]acridine
Dibenz[a,c]anthracene
Dibenz[a ,h]anthracene
Dibenzo[a ,i]pyrene
COKE
OVEN EMISSIONS*
Activationt
A,
N.
A
A,
A,
A
A
A,
A,
A,
A,
A,
A
A,
A
A
PB
A.
PB
PB
PB
PB
PB
PB
PB
PB
Reported
Response§
+b
+c
-a,+c
_a,b,c
+a,b,c
+a,b,c
+a,b,c
+a,b
+a,b
_b,c
_b
+a,b,c
+a
+a,b
+a,b
+a,b
*Content of coke oven emissions extracted from reports by Bjorseth
et al. (1978) and U.S. EPA (1977b).
tA, Aroclor-induced; PB, pnenobarbital-induced; N.A., not available.
§Data were interpreted in the reference:
a, reported by McCann et al. (1975)
b, reported by Kaden et al. (1979)
c, reported by Epler et al. (1979)
(continued on the following page)
49
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TABLE IV-2. (continued)
Chemical
Fluoranthene
Fluorene
Indole
I soqu incline
Naphthalene
Naphthylamine
Peryl ene
Phenanthrene
Pyrene
Pyridine
Qu incline
Triphenylene
S-9 Activationt
A
A, PB
A, PB
A, PB
A, PB
A
A
A, PB
N.A.
A, PB
A
A
Reported
Response§
+b,c
_a,b
_b
_b,c
_a,b,c
+a,c
+b
_a,b,+c
+c
+b
+b,c
+b,c
tA, Aroclor-induced; PB, phenobarbital-induced; N.A., not available
§Data were interpreted in the reference:
a, reported by McCann et al. (1975)
b, reported by Kaden et al. (1979)
c, reported by Epler et al. (1979)
50
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or negative in the Salmonella/microsome assay. [A positive response in this
test appears to be highly correlated with the carcinogenic potential of
chemical substances (McCann et al. 1975)]. The chemicals listed in Table IV-2
may or may not be major constituents of coke oven emissions and may or may not
significantly contribute to the mutagenic potential associated with
simultaneous exposure to the complex mixture itself. Some of the possible
organic constituents identified in coke oven emissions, which may be
responsible for the potential mutagenic hazards in the complex mixture, are
the polycyclic aromatic hydrocarbons (such as benzopyrenes and chrysene), the
heterocyclic nitrogen compounds (such as pyridines, quinoline and substituted
quinolines, acridine), or aromatic amines (such as B-naphthylamine) (Epler et
al. 1977, McCann et al. 1975, Hollstein et al. 1979, U.S. EPA 1980a, Brooks
1977, Kimball and Munro 1981).
The listing above is by no means inclusive. Although several individual
coke oven components have been shown to induce mutagenic responses in certain
tests (e.g., bacteria, yeast, mammalian cells In vitro, animals), interactions
(e.g., synergisms and antagonisms) may occur among the other components in
the complex mixture to alter their mutagenic potential (Rao et al. 1979, Hass
et al. 1981, Pelroy and Peterson 1979).
SUMMARY AND CONCLUSIONS
The complex mixture, coke oven emissions, has been tested for its
mutagenic potential only in the Salmonel1 a/mammalian microsome assay. The
solvent-extracted organics caused mutations in a dose-dependent manner in
frameshift-sensitive strains. The incorporation of an exogenous mammalian
microsomal activation system greatly enhanced the mutagenic activity of this
complex mixture. To confirm the positive responses reported in Salmonella,
51
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further testing in other organisms (e.g., mammalian cells in culture) is
necessary. It is important to point out that several known mutagens,
identified as positive in various genetic test systems, have been identified
in coke oven emissions and could contribute to the mutagenicity of the whole
mixture. Like coke oven emissions, many of these components are primarily
detected in Salmonella as frameshift-acting mutagens after metabolic
activation. Also in support of coke oven mutagenicity, a related complex
mixture, sampled from the coke oven collecting main, has been shown to be
positive in two different organisms (namely, bacteria and mammalian cells in
culture). This complex material was also detected in bacteria as
frameshift-acting after metabolic activation.
In conclusion, the weight of evidence (i.e., in vitro data regarding the
mutagenic activity of coke oven emissions and a related complex mixture and
the data regarding the mutagenic activity of the individual components
identified in coke oven emissions) suggests that coke oven emissions may have
the potential to cause somatic mutations in humans. It should be emphasized,
however, that the complex mixture itself, coke oven emissions, was evaluated
only in an in vitro test; and when evaluating the risk posed by exposure to a
mutagenic agent, several factors (e.g., absorption, metabolism,
pharmacokinetics) may alter the mutagenic response in the whole mammal
compared to the mutagenic potential determined in an in vitro test.
CELL TRANSFORMATION
Currently available studies concerning the ability of topside coke oven
extract to cause cell transformation are derived from the EPA diesel research
program (Huisingh et al. 1979). The sample tested was collected on top of a
coke oven battery and was shown to cause cell transformation in BALB/c 3T3
52
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cells and in primary Syrian hamster embryo cells with viral enhancement by
Simian adenovirus (Curren et al. 1979, Casto et al. 1979). Negative results
were reported with one test conducted in primary Syrian hamster embryo cells
using the focus assay method. Because of the location of the topside air
sampler and local wind conditions, an unknown portion of the topside coke oven
sample contained particulate matter from other ambient air sources, as
previously discussed in the mutagenicity section herein. Hence, the extent to
which the results of the above cell transformation studies are representative
of the topside coke oven alone appears uncertain.
53
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V. TOXICITY
Coke oven emissions consist of a complex mixture of organic and inorganic
gases and participates (Table II-l). Only coal tar, which is produced by the
condensation of coke oven emissions, will be discussed in this section.
Constituents of emissions other than those producing coal tar are not
considered essential to the discussion of toxicity in this document.
ACUTE TOXICITY OF COAL TAR
Experimental toxicity data on the noncarcinogenic toxic effects of coal
tar are limited. In a review by Graham et al. (1940; cited in NIOSH 1978), an
early study was cited in which feeding of coal tar products to pigs (6 to 15
g/day for 5 days) produced extensive liver damage and 100% mortality in the
five treated animals. A second study involving the administration of liquid
coal tar in capsules to pigs (three pigs receiving 3 g/day for 5 days; two
pigs receiving 3 g/day for 2 days) produced similar results.
SUBCHRONIC AND CHRONIC TOXICITY OF COAL TAR AEROSOLS
In 1973, the National Institute for Occupational Safety and Health
published a criteria document concerning occupational exposure to coke oven
emissions. A major conclusion reached in that report was that dose-response
data were lacking on the toxicity of coke oven emissions. In response to this
need for more definitive information, several studies were subsequently
undertaken to determine the response of experimental animals to measured
concentrations of coal tar aerosols collected from coke ovens.
Kinkead (1973) prepared an aerosol of coal tar in which the solids
previously had been removed by centrifugation. He exposed 64 Sprague-Dawley
yearling rats (32 male and 32 female), 64 Sprague--Dawley weanling rats
54
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(32 male and 32 female), 50 male ICR mice, and 50 male CAF-1 mice continuously
for 90 days at concentrations of 0.2, 2.0, and 10 mg/m3. In addition, 80
yearling female Sprague-Dawley rats, 9 weanling rats of each sex, 25 male
CAF-1 mice, 25 male ICR mice, 24 female New Zealand white rabbits, and 100
male Syrian golden hamsters were exposed continuously for 90 days at 20
mg/m3. Greater than 95% of the aerosol droplets were 5 urn or less in
diameter. Nominal and measured exposure levels were comparable.
The author stated, without reporting his data, that considerable mortality
among exposed animals was encountered in this study. Mortality patterns were
attributed to debilitation from exposure leading to greater susceptibility to
infection, and a high incidence of chronic murine pneumonia was found in all
species under study. Cumulative mortality was reported to be proportional to
exposure concentration.
In all species tested, there was a remarkable effect of exposure on body
weight growth curves. Weight loss was evident in exposed mice during
exposure, and body weight gain was lower in treated mice compared to control
mice following exposure (Figures V-l and V-2). Trends in body weight
reduction in adult rats, hamsters, and rabbits were stated (data not reported)
to have been similar to those found in treated mice. Body weight loss was
also evident in exposed weanling rats (Figures Y-3 and Y-4). However, in
contrast to treated mice, decreased body weight gain rather than marked loss
occurred during treatment, and a dose-response in reduced body weight gain is
clearer for weanling rats. Even the lowest exposure concentration, 0.2
ug/m3, produced some adverse effects on body weight gain. Following the
termination of exposure, the inhibitory effect of coal tar aerosol on growth
was still evident for at least 7 months in most species.
Kinkead conducted a subsequent coal tar experiment in which the solid
55
-------
40 r
z
2
UJ
0
o
CO
tr
UJ
2.Q mg/m3
10 mg/m3
O 20 mg/m3
Figure V-l. Growth of male CAF-1 mice exposed to coal tar aerosol
(Kinkead 1973)
56
-------
I
2
uu
Q
§
01
s
oc
UI
45
40
35
30
25
0.0 mg/m3
——— 0.2 mg/m3
—— A 2.0 mg/m3
• 10 mg/m3
O 20 mg/m3
EXPOSURE-
-POST EXPOSURE-
123456789 10
DURATION (months)
Figure V-2. Growth of male ICR mice exposed to coal tar aerosol
(Kinkead 1973)
57
-------
650
I
o
0
s
UJ
o
<
IT
LU
0.0 mg/m3
0.2 mg/m3
A 2.0 mg/m3
• 10 mg/m3
O 20 mg/m3
-EXPOSURE
POST EXPOSURE-
23456789 10
DURATION (months)
Figure V-3. Growth of male weanling rats exposed to coal tar aerosol.
(Kinkead 1973)
58
-------
380 r
340
300
- 260
I-
i 220
Q
O
o
Ml
s
EC
UJ
180
140
100
60'
0.0 mg/m3
0.2 mg/m3
ZO mg/m3
10 mg/m3
20 mg/m3
I
234 567
DURATION (months)
9 10
Figure V-4. Growth of female weanling rats exposed to coal tar aerosol
(Kinkead 1973)
59
-------
particles and light oil fractions were retained in the experimental aerosol.
Sprague-Dawley rats, New Zealand white rabbits, JAX mice, and Syrian golden
hamsters (numbers not specified) were exposed continuously for 90 days to the
coal tar aerosol at a concentration of 10 mg/m3. In addition, 150 CF-1 mice
were exposed to the aerosol and serially sacrificed for histopathologic
analysis. Among exposed rats and hamsters, McDonnell and Specht (1973)
described three significant lesions occurring at the termination of exposure.
These were: 1) phagocytized coal tar pigment in alveolar macrophages and in
the peribronchial lymphoid tissue; 2) hepatic and renal hemosiderosis which
disappeared by 100 days post-exposure; and 3) mild central lobular necrosis in
the liver. Among mice sacrificed 99 days post-exposure, moderate pigmentation
of alveolar macrophages was observed in 14 of 15 CF-1 mice, but in only 1 of
13 exposed JAX mice.
In a follow-up study, MacEwen and coworkers (1976) prepared a composite
coal tar mixture collected from multiple coking ovens around the greater
Pittsburgh area. Coal tar samples were blended together with a 20% by volume
amount of the BTX (benzene, toluene, xylene) fraction of coke oven distillate.
This material was believed to be more representative of that inhaled by
workers on top of coke ovens. Female (75) ICR-CF-1 mice, female (50)
CAF-1-JAX mice, male (40) and female (40) weanling Sprague-Dawley rats, New
Zealand white rabbits (18), and male (5) and female (9) Macaca mullata monkeys
were exposed to a coal tar aerosol at 10 mg/m3, 6 hours daily, 5 days/week,
for 18 months. Animals were held for an additional 6-month observation period
following termination of exposure. A significant inhibition of body growth
rate was observed for both male and female rats after 4 months and for rabbits
by the end of the first month (Figures V-5 and V-6). Monkeys showed no
significant inhibition of growth rate from exposure to the coal tar aerosol
60
-------
Figure V-5. The effect of repeated exposure to 10 mg/m^ coal tar aerosol on
growth of rats.
(MacEwen et al. 1976)
61
-------
•.Or
• I
Figure V-6. The effect of repeated exposure to 10 mg/m3 coal tar aerosol
on growth of rabbits and monkeys.
(MacEwen et al. 1976)
62
-------
(Figure Y-6). In this study, 16 of 18 test rabbits and 6 control rabbits died
during the test period.
A description of toxic effects of compounds and classes of compounds
described in Table II-l can be found in Dreisbach (1977), U.S. EPA documents
(1977a, 1978a-c, 1979, 1980a-n), World Health Organization (1979), Venugopal
and Luckey (1978), Roy and Trudinger (1970), National Research Council (1981),
Goldstein et al. (1980), and Carcinogen Assessment Group (1980a).
63
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VI. CARCINOGENICITY
HUMAN EPIDEMIOLOGY STUDIES
The American long-term mortality study of coke oven workers by Lloyd,
Redmond, and coworkers (Lloyd and Ciocco 1969, Lloyd et al. 1970, Lloyd 1971,
Redmond et al. 1972, Redmond et al. 1976, Mazumdar et al. 1975, Redmond et al.
1979) found that workers exposed to coke oven emissions have an increased risk
of cancer mortality. Sakabe et al. (1975) found that coke oven workers who were
retired from iron and steel plants in Japan, had an excess risk of lung cancer
mortality when compared to the Japanese male population. British studies by
Reid and Buck (1956), Davies (1977), and Coll ings (1978) have not demonstrated
the cancer risk found in the American studies or the Sakabe et al. study, but
the British studies had some design limitations, including short follow-up
periods and lack of delineation of the coke oven workers by work area, that may
have prevented the detection of any cancer risks.
American Studies
In 1969 Lloyd and Ciocco began a long-term study of the mortality of
steelworkers in Allegheny County, Pennsylvania. Subsequent updates of this
study focused on the mortality of coke oven workers. In 1972 Redmond et al.
expanded the study to include coke plants at ten steel plants throughout the
United States and Canada. Because there are several updates of the study, a
summary table has been prepared and precedes the discussions of the studies
(Table VI-1).
Lloyd and Ciocco (1969)--
In 1969 Lloyd and Ciocco reported on the mortality of approximately 59,000
steelworkers, including coke oven workers, employed in 1953 at seven steel
plants in Allegheny County, Pennsylvania. Mortality was reported by age, race,
64
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TABLE VI-1. SUMMARY OF COKE OVEN MORTALITY STUDY BEGUN BY
LLOYD AND CIOCCO (1969)
Author and
Year of Report
Study
Population
Comparison
Group
End of Follow-up
on Vital Status
Findings
Lloyd and
Ciocco (1969)
Lloyd et al.
(1970)
Lloyd (1971)
Steelworkers at
seven plants in
Allegheny County,
Pennsylvania
employed in 1953
Different job
categories within
the steelworker
population em-
ployed at seven
plants in
Allegheny County,
Pennsylvania
in 1953
Steelworkers
employed in 1953
who worked or
previously had
worked in the
coke plant at
two Allegheny
County,
Pennsylvania
steel plants
Allegheny County
male population
in 1953
All steelworkers
employed at seven
steel plants in
Allegheny County
in 1953
December 31, 1961
December 31, 1961
All steelworkers
employed at seven
steel plants in
Allegheny County
in 1953
December 31, 1961
Average annual crude
mortality rates were lower
among the steelworkers than
among the male population of
Allegheny County.
Nonwhite coke plant workers
employed at least 5 years
had a significantly higher
total mortality rate (96
observed, 78.7 expected,
P < 0.05), and a signifi-
cantly (P < 0.05) higher
cancer mortality rate (40
observed, 19.6 expected,
P < 0.01); most of the
excess cancer mortality was
due to lung cancer mortality
(25 observed, 7.3 expected).
An increase in respiratory
neoplasm deaths was found
for all coke oven workers
as well as a significant
excess of mortality, all
causes, for workers who
had worked full-time top-
side. The respiratory
cancer excess was signifi-
cant (P < 0.01) only among
nonwhite workers. A dose-
response for respiratory
cancer mortality was
evident by work area for
workers who had worked 5
or more years.
65
(continued on the following paqe)
-------
TABLE VI-1. (continued)
Author and
Year of Report
Study
Population
Comparison
Group
End of Follow-up
on Vital Status
Findings
Redmond et al.
(1972)
Coke oven workers
empl oyed at two
Allegheny County,
Pennsylvania
steel plants
1n 1953.
Coke oven workers
employed at 10
non-Allegheny
County steel
plants from 1951-
55.
Al1 men who
never worked
at the coke
ovens at the
respective
Allegheny
County
steel plants.
Nonoven workers
employed at the
respective non-
Allegheny County
steel plants
from 1951-55.
December 31, 1966
A significant excess in
respiratory cancer deaths
was found for the non-
Allegheny County plants (33
observed, 20.7 expected,
P < 0.01); the Allegheny
County plants continued
to have a significant
(P < 0.01) excess of respi-
ratory cancer deaths.
Deaths from malignant
neoplasms of the genito-
urinary system were found
to be significantly (10
observed, 5.7 expected,
P < 0.05) in excess among
nonwhites in the non-
Allegheny County plants and
significantly (5 observed,
observed, 0.9 expected,
P < 0.01) in excess among
whites in the Allegheny
County plants. Lung cancer
followed a dose-response
by work area (topside,
part-time topside, or side
oven only) for all workers
who had worked 5 years or
more at the coke ovens.
For nonwhites at all
plants, lung cancer was
found to follow a dose-
response by length of time
worked (< or > 5 years).
(continued on the following page)
66
-------
TABLE VI-1. (continued)
Author and
Year of Report
Study
Population
Comparison
Group
End of Follow-up
on Vital Status
Findings
Mazumdar et
al. (1975)
Redmond et
al. (1976)
Coke oven workers
employed at two
Allegheny County,
Pennsylvania
steel plants
in 1953.
Coke oven workers
employed at 10
non-Allegheny
County steel
plants from 1951-
55.
Steel workers
employed at
seven Allegheny
County,
Pennsylvania
steel plants in
1953 who worked
in the coke plant
prior to or during
1953.
Al 1 men who never
worked at the
coke ovens at the
respective
Allegheny County
plants.
Nonoven workers
employed at the
respective non-
Allegheny County
steel plants
from 1951-55.
December 31, 1966
All steel workers
employed at the
seven Allegheny
County,
Pennsylvania
steel plants in 1953.
December 31, 1970
A considerable difference
in exposure to coal tar
pitch volatiles was found
for different work areas.
The level of exposure and
length of time exposed were
both found to be related
to the development of
cancer, particularly lung
cancer.
The statistically signifi-
cant excess of respiratory
cancer mortality and cancer
mortality, all sites,
continued. Length of
exposure was divided by 5+,
10+, and 15+ years. A
clear dose-response was
evident both by length of
exposure and by work site.
(continued on the following page)
67
-------
TABLE VI-1. (continued)
Author and
Year of Report
Study
Population
Comparison
Group
End of Follow-up
in Vital Status
Findings
Redmond et
al. (1979)
Steelworkers em-
ployed at seven
Allegheny County,
Pennsylvania
steel plants in
1953 who worked
in the coke plant
prior to or
during 1953.
Coke oven workers
employed at 10
non-Allegheny
County steel
plants from
1951-1955.
All steelworkers
employed at the
seven Allegheny
County steel
plants in 1953.
December 31, 1975
Non-coke oven
workers employed
at the respective
non-Allegheny
County steel
plants from
1951-1955.
Workers ever employed at
the Allegheny County coke
ovens through 1953 had a
significant excess of
deaths from "cancer-all
sites" (179 observed, 144.4
expected, P < 0.01), prostate
cancer (20 observed, 12.7
expected, P < 0.05), and
kidney cancer (7 observed,
2.6 expected, P < 0.05). The
elevated lung, trachea, and
bronchus cancer mortality
seen in the earlier updates
continued.
Among non-Allegheny County
coke oven workers, a
significant excess of cancer
mortality at all sites (194
observed, 162.56 expected,
P < 0.01) and a significant
excess of prostate cancer
mortality among nonwhite
workers (15 observed, 9.44
expected, P < 0.05) was
found. As in the Redmond et
al. (1972) update, a signifi-
cant (P < 0.05) excess of
lung, trachea, and bronchus
cancer mortality existed for
both whites and nonwhites.
Excesses increased for
workers employed 5 or more
years.
68
-------
and cause of death. Mortality was not divided by work area (e.g., coke oven
workers, etc.), however. Records of the workers were collected between July
1962 and December 1964 at the personnel offices of the plants by teams of four
people assigned to each plant. Information on workers who still worked at the
plant in 1962 included a complete work history from time of first employment
with the specific company through 1961, birthplace of employee and his parents,
race, marital status, and identifying information for follow-up. For men
leaving employment before January 1, 1962, the follow-up schema consisted of
references to death lists and city directories, as well as inquiries to local,
state, and federal agencies. When no determination could be made through these
sources, mail and telephone contacts were made to the next of kin. The average
annual mortality rates for the steelworkers were found to be lower than that of
the male population of the county in which the plants are situated. For the
steelworkers, the crude mortality rate among whites was 911.0 per 100,000
person-years at risk and among nonwhites was 994.2 per 100,000 person-years at
risk. In the county where the steel plants are located, the crude mortality
rate among whites was 1578.2 per 100,000 population and among nonwhites was
1880.6 per 100,000 population. Comparison by age category found that for both
whites and nonwhites, the mortality rates were higher in the county than among
the steelworkers.
Lloyd et al. (1970) —
In a continuation of the Lloyd and Ciocco (1969) study, Lloyd et al. (1970)
calculated the expected deaths for each of 53 work areas by applying the death
rate of the total steelworkers population to the number at risk in the work
area. A Standard Mortality Ratio (SMR)* was calculated for each area. The
*SMR = Observed Deaths x
Expected Deaths
69
-------
overall SMR for coke plant workers was 104. Since disease response may be a
function of length of exposure, an SMR using person-years was calculated for
those who had attained 5 years of exposure. For each man who had attained 5
years in a work area, the time at risk was calculated as the time of completion
of the 5 years to the end of observation (date of death or December 1961). For
men attaining 5 years prior to 1953, the initial date at risk was January 1,
1953. The comparison group was all steelworkers who had attained 5 years of
employment in the industry prior to or during the period 1953-1961. The number
of expected deaths in each work area for specified race, age, nativity (country
of origin), and residence was calculated by applying the specific rate of the
total steelworker population to the person-years at risk in the work area. For
coke plant workers, the SMR for white workers was 99 while the SMR for nonwhite
workers was 122, which was significant (96 observed, 78.7 expected, P < 0.05)
using a summary chi-square with one degree of freedom. When Lloyd et al. looked
at cause-specific mortality among workers exposed 5 years or more, the SMR for
malignant neoplasms among white coke plant workers was 102 while that among
nonwhite workers was 204 (40 observed, 19.6 expected, P < 0.05). The authors
reported that a more detailed analysis of the deaths from malignant neoplasms
revealed that the excess for nonwhite workers was due to malignant neoplasms of
the respiratory system (25 observed vs. 7.3 expected). SMR's for other causes
of death (vascular lesions affecting the central nervous system, heart disease,
accidents, all other causes) were not significant.
Lloyd (1971)--
Lloyd (1971) further delineated the source of the respiratory cancer excess
within the coke plant environment and clarified the apparent differential in
mortality for white and nonwhite workers. All of the coke oven workers in the
70
-------
steelworker study worked at by-product coke ovens. Prior to World War I, the
main source of metallurgical coke in the United States was the beehive coke
oven. Since World War I, the by-product plant, which allows for recovery of
tar, oils, and chemicals from the volatiles, has increasingly predominated. The
by-product coke plant is divided into three rather distinct areas in terms of
function and potential exposure to environmental hazards. These are: 1) the
coal handling area where coal is received by rail or barge and where provision
is made for the handling, storage, and blending of several types of coal before
transfer to the coke ovens; 2) the coke ovens, grouped into batteries, with
equipment for charging and discharging the ovens and the quenching of coke; and
3) the by-product plants for recovery of gas and chemical products. Because of
the reports by Kawai et al. (1967) and Doll et al. (1965) of higher lung cancer
rates for men engaged primarily in the coal-carbonization process, Lloyd decided
to focus on the men employed at the coke ovens or in their immediate vicinity.
Occupational titles indicating employment some distance from the coke ovens were
assigned to a nonoven group. The coke oven group included all job titles
requiring that some part of the working day be spent at the topside of the ovens
or the side of the ovens, including the quenching station, the coke wharf, and
the coke screening station.
Of the 58,828 steelworkers employed in 1953, 2,552 worked in the coke plant.
However, an additional 978 steelworkers employed in other work areas in 1953 had
previously been employed in the coke plant. The distribution of these workers
by race, work area, and period of employment (1953 or prior years) is given in
Table YI-2.
Expected mortality for the coke oven workers was derived from mortality for
the entire steelworker population. A significant excess of observed to expected
deaths from malignant neoplasms of the respiratory system was found (Table
71
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TABLE VI-2. DISTRIBUTION OF COKE PLANT WORKERS EMPLOYED IN ALLEGHENY COUNTY.
PENNSYLVANIA IN 1953 BY WORK AREA AND RACE
(adapted from Lloyd 1971)
Total
White
Nonwhite
Coke Plant
Empl oyed
3.530
2.369
1.161
Coke
Number
in 1953 or
2.048
993
1.055
Oven
Per Cent
Prior Years
58.0
41.9
90.9
Nonoven
Number Per
1.482 42
1.376 58
106 9
Cent
.0
.1
.1
72
-------
VI-3). Although there was an increase in respiratory cancer deaths among white
workers, this increase was not significant. Respiratory cancer deaths among
nonwhite workers was significantly (P < 0.01) elevated. The author reported
that of the 25 deaths from malignant neoplasms of the respiratory system among
workers employed in 1953, 23 of them were attributed to neoplasm of the lung.
The author did not present any data on the specific site of the respiratory
neoplasm deaths among workers employed in years prior to 1953. Coke oven worker
mortality from diseases other than malignant neoplasm of the lung was little
different from expected.
The author next considered differential mortality within the several work
divisions of the coke ovens. To do this he divided the coke oven workers into
full-time topside (larry car operator, "lidman, and standpipe man), part-time
topside (foreman, heater, and occassional maintenance men such as pipefitters),
and side oven, which was the remainder of the coke oven work force (including
workers at the quenching station, coke wharf, and the screening station).
Mortality for malignant neoplasms of the lung for each of these subdivisions is
reported by race in Table VI-4. As can be seen in Table Vl-4, there is a
significant excess of total coke oven worker lung cancer mortality. Nonwhite
lung cancer mortality is significantly increased; white lung cancer mortality is
in excess but not significant. The excess mortality is associated primarily
with employment at the full-time topside occupations. The total mortality
experience of men employed only at the side ovens does not differ significantly
(P < 0.05) from that expected. The observed deaths from malignant neoplasms of
the lung are seven times that expected (19 observed, 2.6 expected, P < 0.01) for
full-time topside workers; the risk for nonwhite topside workers is eight times
that expected (18 observed, 2.2 expected, P < 0.01). The limitation of small
73
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TABLE VI-3. OBSERVED AND EXPECTED RESPIRATORY CANCER DEATHS AND STANDARDIZED
MORTALITY RATIOS (SMR's) OF COKE OVEN WORKERS EMPLOYED IN ALLEGHENY COUNTY, PENNSYLVANIA
IN 1953 AND PRIOR YEARS BY RACE
(adapted from Lloyd 1971)
Coke Plant Coke Oven Nonoven
Observed Expected Observed Expected Observed Expected
Deaths Deaths SMR Deaths Deaths SMR Deaths Deaths SMR
Total 37
White 11
Nonwhite 26
21.8 170* 33 13.3 248* 4 8.5 47
12.2 90 8 5.0 160 3 7.3 41
9.6 271* 25 8.4 298* 1 1.2 ~-t
*Significant at P < 0.01.
tLess than five deaths in both observed and expected; statistical significance not calculated.
74
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TABLE VI-4. OBSERVED AND EXPECTED LUNG CANCER DEATHS AND STANDARDIZED
MORTALITY RATIOS (SMR's) FOR MEN EMPLOYED IN SELECTED COKE OVEN
SUBDIVISIONS IN ALLEGHENY COUNTY, PENNSYLVANIA
IN 1953 AND PRIOR YEARS BY RACE
(adapted from Lloyd 1971)
Observed
Expected
SMR
Total Coke Oven
White
No n white
Side Oven
White
Nonwhite
Partial Topside
White
Nonwhite
Full Topside
White
Nonwhite
31
8
23
10
5
5
2
2
0
19
1
18
12.3
4.7
7.6
8.0
2.7
5.4
1.7
1.6
0.1
2.6
0.5
2.2
252*
170
303*
125
185
93
— t
— t
---t
731*
— -t
818*
'Significant at P < 0.01.
tLess than five deaths in both observed and expected; significance not
calculated.
75
-------
numbers precludes the calculation of significance of the lung cancer excess for
white workers. Causes of death other than malignant neoplasm of the lung were
not significantly (P < 0.05) greater than expected.
Lloyd also looked at observed and expected lung cancer deaths by length of
employment (Table VI-5). Lung cancer mortality among coke oven workers having
worked 5 or more years was significantly (P < 0.01) increased. Although an
excess was found for both white and nonwhite workers, only the excess among the
nonwhite workers having worked 5 or more years was significant. Deaths from
causes other than lung cancer were not significantly (P < 0.05) increased above
that expected.
When the lung cancer mortality of men employed 5 years or more at coke
ovens was analyzed by work area, it was found that full-time topside workers had
ten times the expected number of lung cancer deaths (Table VI-6). The
combination of work area and length of exposure to produce a higher SMR than
that found by either work area or- length of exposure alone suggests that both
length of exposure and intensity of exposure are important respiratory cancer
risk factors.
Other causes of death among the coke oven workers were found to be similar
to expected except for a significant (P < 0.05) excess of "nonrespiratory
tumors" among "side and topside (less than 5 years-topside)" workers (9 observed
vs. 4.3 expected and a SMR of 209), and a significant excess (P < 0.05) of "all
other causes" (11 observed vs. 6.1 expected and a SMR of 180) among nonwhite
full-time topside workers. Most of the excess in "other causes" is accounted
for by deaths from vascular lesions of the central nervous system and
tuberculosis.
A primary criticism of the Lloyd (1971) study is the fact that smoking, a
potential confounding variable in any study of lung cancer, was not adequately
addressed primarily due to the nature of the study design. Obtaining smoking
76
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TABLE VI-5. OBSERVED AND EXPECTED LUNG CANCER DEATHS AND STANDARDIZED
MORTALITY RATIOS (SMR's) FOR MEN EMPLOYED AT COKE OVENS IN ALLEGHENY
COUNTY, PENNSYLVANIA IN 1953 AND PRIOR YEARS BY LENGTH
OF EMPLOYMENT (AS OF JANUARY 1, 1953)
(adapted from Lloyd 1971)
Observed
Expected
SMR
Less Than 5 Years
White
Nonwhite
5 or More Years
White
Nonwhite
4
3
1
27
5
22
4.7
2.2
2.6
7.6
2.6
5.1
— t
— t
— t
355*
192
431*
"Significant at P < 0.01.
ttess than five deaths in both observed and expected; significance not
calculated.
TABLE VI-6. OBSERVED AND EXPECTED LUNG CANCER DEATHS AND STANDARDIZED
MORTALITY RATIOS (SMR's) FOR MEN EMPLOYED AT COKE OVEN
SUBDIVISIONS IN ALLEGHENY COUNTY, PENNSYLVANIA FOR MORE
THAN 5 YEARS (AS OF JANUARY 1, 1953) BY WORK AREA AND RACE
(adapted from Lloyd 1971)
Observed
Expected
SMR
Side Oven Only
White
Nonwhite
6
2
4
4.1
1.1
3.0
146
— -t
— t
Side and Topside
(less than 5 years
full topside)
White
Nonwhite
Full-time Topside
White
Nonwhite
6
2
4
15
1
14
2.1
1.3
0.8
1.5
0.2
1.3
286*
— t
... f
1000*
•)•
1077*
"Significant at P < 0.01.
tLess than five deaths in both observed and expected; significance not
calculated.
77
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histories in a study of historic prospective design is nearly impossible.
However, the dose-response is so pronounced in this study, particularly for
nonwhite workers, that it is improbable that the significant excess seen in lung
cancer mortality could have been caused by smoking alone. Certainly, however,
the possibility of a synergistic effect of smoking and coke oven emissions
cannot be ruled out.
Lloyd (1974) compared age-specific lung cancer mortality rates of the
steelworkers including the coke oven workers with lung cancer rates for smokers
and nonsmokers (Table VI-7). While the total steelworker population showed a
lung cancer mortality somewhat like that observed for all cigarette smokers and
coke oven workers who never worked topside showed rates not too different from
those for heavy cigarette smokers, the rates for topside workers and for those
employed more than 5 years topside are far beyond what would have been predicted
by differential cigarette smoking experience. Again, a synergistic effect of
coke oven emissions and smoking cannot be ruled out.
78
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TABLE VI-7. ESTIMATES OF AVERAGE ANNUAL LUNG CANCER MORTALITY RATES
(PER 100,000 PERSON-YEARS) FOR SELECTED U.S. SMOKING GROUPS, 1954-1962,
AND STEELWORKER GROUPS, 1953-1961
(Lloyd 1974)
U.S. Smokers
A
G
E Steel workers
Never smoked or occasional only
Current cigarette smokers - total
Current cigarette smokers, 1-9/day
Current cigarette smokers, over 39/day
35.44 45.54 55-64
<45 45-54 >55
12
5 39 158
69
104 321
65-74
29
258
119
559
Steel workers
Coke oven, never topside
Coke oven, topside
Coke oven, > 5 years topside
12
228
265
126
130
1,058
1,587
160
387
1,307
1,961
79
-------
Redmond et al. (1972)--
Redmond et al. (1972) expanded the investigation of coke oven workers to
include ten selected steel plants in diverse parts of the United States and
Canada. Study subjects included men who had worked at the coke ovens at these
plants at any time in the 5-year period 1951 through 1955. Criteria used to
determine eligibility for inclusion in the study as a coke oven employee were as
follows: 1) the man must have had at least 30 consecutive days of employment at
the coke ovens, and 2) individuals listed strictly as vacation replacements were
not eligible. The comparison group of men was chosen in one of two ways.
First, at plants where permanent numbers were assigned sequentially at time of
first employment, the nonoven workers were selected by examining the records of
the men closest in number to the coke oven workers. The first two men who were
employed at the same plant during the period 1951 through 1955, of the same
race, and of similar date of initial employment of the coke workers were chosen
for the comparison group (i.e., two nonoven workers for each oven worker). At
four plants no sequential number was assigned on the basis of starting date;
therefore, a second method for selecting the comparison group was devised. A
systematic sampling of one out of every five records was made and two nonoven
workers were selected for each oven worker on the basis of closest starting
date, race, and other study criteria which included the following: 1) the man
must have been actively employed sometime in the period 1951 through 1955; 2)
the man must never have held a job at the coke ovens, but could have worked in
the coal, coke handling, or by-products areas; 3) the man must have had at least
30 days consecutive employment; and 4) vacation replacements were excluded.
Since occupational terminology varied from plant to plant, personnel at the
plant were consulted to clarify whether the job in question was at the coke
ovens. Follow-up of the workers was through December 31, 1966. For workers who
80
-------
had left employment prior to December 31, 1966, the method of ascertaining vital
status was similar to that of Lloyd and Ciocco (1969). Among all coke plant
(oven and nonoven) workers there was a loss to follow-up of only 18 of 2,888
(0.6%) for white employees and 62 workers out of 3,587 (1.7%) for nonwhite
employees. In addition to the investigation of the ten non-Allegheny County
steel plants, follow-up of all workers who had worked during 1953 at the two
Allegheny County steel plants that had coke plants (reported by Lloyd 1971) was
updated to 1966. The comparison group for the Allegheny County steel plants
consisted of all men who had never worked at the coke ovens.
Expected mortality and relative risk for the coke oven workers were derived
in the following manner:
Tables have been constructed for the coke oven workers and controls by
first classifying each plant's cohort by race, age at entry to the study,
and the calendar years of follow-up: 1951-1957, 1958-1962, 1963-1966. An
expected number of deaths for the coke oven workers was calculated for
each of these subgroups with the underlying assumption that both coke oven
workers and controls have the same rate within each subgroup. The total
expected number of deaths for each plant is the sum of the specific rates
for each subgroup multiplied by the number of coke oven workers at risk in
the subgroup, while the expected number of deaths for coke oven workers at
all plants is the sum of the expected number of deaths for the individual
plants. The relative risk is a weighted average of the observed and
expected number of deaths for each subgroup, where the weights used are
approximately proportional to the precision within each subgroup. The
reader should note that, because the relative risk is a weighted average,
it cannot be obtained directly by dividing the total observed deaths by the
total expected deaths.
Comparison of observed and expected deaths for all workers revealed an
excess of malignant neoplasms of the lung, trachea, and bronchus and of the
genitourinary organs (Table VI-8). Among the non-Allegheny County workers, a
significant excess in lung, trachea, and bronchus cancer deaths occurred in both
white and nonwhite workers. In addition, a significant (P < 0.05) excess in
genitourinary cancer was found among nonwhite workers. As Lloyd (1971) had
found, mortality from cancer of the lung, trachea, and bronchus among Allegheny
County workers was significant (P < 0.01) for nonwhites only. Genitourinary
81
-------
TABLE VI-8. OBSERVED AND EXPECTED DEATHS AND RELATIVE RISKS FOR MALIGNANT NEOPLASMS OF THE LUNG, TRACHEA,
AND BRONCHUS AND THE GENITOURINARY ORGANS FOR COKE OVEN WORKERS EMPLOYED FROM 1951 TO 1955
AT TEN NON-ALLEGHENY COUNTY STEEL PLANTS AND FOR COKE OVEN WORKERS EMPLOYED DURING
1953 AT TWO ALLEGHENY COUNTY, PENNSYLVANIA STEEL PLANTS BY RACE
(adapted from Redmond et al. 1972)
Non-Allegheny County
Allegheny County
All Plants
Observed Expected Relative Observed Expected Relative Observed Expected Relative
Deaths Deaths Risk Deaths Deaths Risk Deaths Deaths Risk
Malignant Neoplasms
Lung, trachea, and 13 7.5 3.02*
bronchus
Malignant Neoplasms
Genitourinary organs 2 1.8 —§
WHITE
3.4
0.9
—§
6.99
17
10.8
2.7
2.06t
3.49t
Malignant Neoplasms
Lung, trachea, and 23 13.4 2.99t 29
bronchus
Malignant Neoplasms
Genitourinary organs 10 5.7 3.02t 4
NONWHITE
17.3
4.9
3.77t
—§
52
14
30.7
10.6
3.35t
1.60
Malignant Neoplasms
Lung, trachea, and
TOTAL
bronchus
Malignant Neoplasms
Genitourinary organs
36
12
20.9
7.5
3.00t
2.42*
33
9
20.7
5.8
2.69t
1.76
69
21
41.5
13.3
2.85t
2.05t
*Sigmncant at P < 0.05 as calculated t>y a summary cm-square statistic with one degree of freedom.
tSignificant at P < 0.01 as calculated by a summary chi-square statistic with one degree of freedom.
§Less than five deaths in both observed and expected; significance not calculated.
-------
cancer mortality among Allegheny County workers was significant (P < 0.01) for
whites only. All other causes of death (other malignant neoplasms, tuberculosis
of the respiratory system, other diseases of the respiratory system,
cardiovascular-renal diseases, accidents, and all other causes) for both
Allegheny and non-Allegheny County workers, were not significantly (P < 0.05)
different from that expected.
As in the Lloyd (1971) study, the authors delineated the mortality
experience by work area and length of exposure. When the cancer mortality for
all plants combined (Allegheny County and non-Allegheny County plants) was
analyzed by work area, a significant (P < 0.05) excess of malignant neoplasms of
the lung, trachea, and bronchus was evident in full-time topside workers with
most of this excess occurring among nonwhite workers. Additionally, there was a
significant (P < 0.05) excess of genitourinary cancer in side oven workers.
Mortality from other causes was not significantly (P < 0.05) different from
expected except for cardiovascular renal disease which was significantly less
than expected among white topside workers and total (white and nonwhite) side
oven workers.
When deaths were analyzed by time spent at the coke ovens, a significant
(P < 0.01) increase in malignant neoplasms of the lung, trachea, and bronchus
and for workers having worked 5 years or more was found, with most of this
excess among nonwhite workers. A significant (P < 0.05) excess of genitourinary
cancer deaths occurred among workers having worked 5 or more years with most of
the excess occurring among white workers (6 observed, 2.2 expected, P < 0.01 for
white workers; 11 observed, 8.4 expected, P > 0.05 for nonwhite workers).
Mortality from other causes was not significantly different from expected except
for "other malignant neoplasms," which was significantly (P < 0.01) less than
expected among workers having worked less than 5 years.
83
-------
As Lloyd (1971) had done, Redmond et al. analyzed the combined effect of
length of employment and work area. Similar to Lloyd's (1971) findings,
malignant neoplasms of the lung, trachea, and bronchus were found to be elevated
for all oven workers having worked 5 years or more, and this excess was found to
follow a dose-response relationship (Table VI-9). Men employed at full-time
topside jobs (subjecting the employee to the greatest exposure) 5 years or more
have a relative risk of cancer of the lung, trachea, and bronchus of 6.87
(P < 0.01), compared with a lesser risk of 3.22 (P < 0.01) for men with 5 years
or more of mixed topside and side oven experience, and 2.10 (P < 0.05) for men
with more than 5 years of side oven experience.
A significant excess (8 observed, 2.6 expected, P < 0.01) of kidney cancer
was found for total oven workers. Lloyd (1971) had found an excess of kidney
cancer, but this excess had not been statistically significant.
Mazumdar et al. (1975)--
Mazumdar et al. (1975) used the mortality data from the Lloyd and Redmond et
al. studies and data compiled by the Pennsylvania Department of Health on
ambient levels of benzene soluble organic (BSD) material for the topside and
side oven areas of the coke oven to analyze cancer mortality dose-response among
the coke oven workers. The authors determined an exposure level in
mg/m3-month of BSD material for the workers by multiplying the exposure for
the area where the person worked (mg/m3) times the length of time in months
that the person worked there. Cumulative exposure (mg/m3-months) was divided
into four categories: _< 199, 200-499, 500-699, and 2. 700 mg/m3-months.
Age-adjusted data for the total number of nonwhite workers showed a clear
dose-response relationship for lung cancer mortality and cancer at all sites
mortality above 200 mg/m3_month. A dose-response was not seen for white
84
-------
TABLE VI-9. OBSERVED AND EXPECTED DEATHS AND RELATIVE RISK FOR NEOPLASMS OF THE LUNG, TRACHEA, AND
BRONCHUS AND KIDNEY FOR COKE OVEN WORKERS EMPLOYED FROM 1951 to 1955 AT TEN NON-ALLEGHENY
COUNTY STEEL PLANTS AND FOR COKE OVEN WORKERS EMPLOYED DURING 1953 AT TWO ALLEGHENY
COUNTY, PENNSYLVANIA STEEL PLANTS BY LENGTH OF EMPLOYMENT
(adapted from Redmond et al. 1972)
Malignant
Neoplasm
Total Oven
Five Years or More
Coke Oven
Five Years or More
Ful 1-Time Topside
Observed Expected Relative
Deaths Deaths Risks
Observed Expected Relative
Deaths Deaths Risks
Observed Expected Relative
Deaths Deaths Risks
Lung, trachea,
and bronchus
Kidney
69
8
41.5
2.6
2.85*
7.49*
55
5
28.0
1.6
3.48*
5.69
25
0
7.4
0.1
6.87*
— §
Five Years or More
Topside and Side Oven Exposure
Five Years or More Side
Oven, Never Topside
Less Than Five Years
Coke Oven
Lung, trachea,
and bronchus
Kidney
15
5.5
0.4
3.22*
—§
15
8.7
0.7
2. lOt
—§
14
0
9.9
0.2
1.70
*Significant at P < 0.01, significance based on a summary chi-square with one degree of freedom.
tSignificant at P < 0.05, significance based on a summary chi-square with one degree of freedom.
§Less than five deaths in both observed and expected; significance not calculated.
85
-------
workers. Fewer white workers than nonwhite workers worked at the topside of the
coke ovens, however, which would have reduced the probability of detecting a
cancer risk for whites in the high exposure group and thus would have reduced
the probability of detecting a cancer mortality dose-response. Also, the
authors stated that "since time, as well as level of concentration, is necessary
to achieve a high-value exposure index, any oven worker dying from lung cancer
within a moderate or small period of time from first exposure can, obviously, no
longer accumulate additional exposure. Consequently, if the total exposure
doses required to increase the risk of lung cancer in a white individual are
less than in the nonwhite individual and/or the average latent period is shorter
than that of the nonwhite worker, the same strong association between total
exposure and increasing risk of lung cancer will not be demonstrated by a time
dependent index such as the one employed here."
Mazumdar et al. found that lung cancer mortality was less than expected for
workers exposed to _< 200 mg/m^-month benzene-soluble material. This should
not be construed as a no effect level, however, because as the authors
themselves stated, a diluting effect may result from inclusion in the study
group of coke oven workers with too few years of observation to allow for the
appearance of a latent effect. The workers in this study were followed for a
period of only 14 years and, as the authors themselves indicate, the average
latent period for occupational lung cancers may range from 15 to 25 years.
Redmond et al. (1976)--
Redmond et al., in an update of the historical prospective cohort study
begun by Lloyd, confirmed earlier findings of a statistically significant excess
of lung cancer in coke oven workers. Follow-up was extended through December
31, 1970, on 58,828 men employed at seven Allegheny County steel plants in 1953
86
-------
and was more than 99.9% complete with some 12,818 men reported deceased.
Expected deaths and relative risk were calculated in the same manner as in the
Redmond (1972) study.
The excess of respiratory cancer found in the Redmond et al. (1972) study
continued. With the longer period of follow-up and the aging of the cohort, the
greater number of deaths made it possible to consider 10+ and 15+ years of
exposure as well as 5+ years. Observed deaths from cancer of the respiratory
system and the relative risks for coke oven workers are shown in Table VI-10.
As can be seen from the table there was a pronounced dose-response both by
length of exposure and by work site. A strong dose-response for cancer
mortality, all sites, was also found by length of exposure and by work site
(Table VI-11).
87
-------
TABLE VI-10. OBSERVED DEATHS AND RELATIVE RISKS OF DEATH FROM
CANCERS OF THE RESPIRATORY SYSTEM, 1953-1970, FOR COKE OVEN
WORKERS BY WORK AREA AND LENGTH OF EMPLOYMENT THROUGH 1953
(adapted from Redmond et al. 1976)
Work Area
Coke Oven
Oven Topside Full-time
Oven Topside Part-time
Oven Side Only
*Significant at P < 0.01.
tSignificant at P < 0.05.
Obs.
54
25
12
17
Years
5+
R.R.
3.02*
9.19*
2.29*
1.79t
Employed Through
10+
Obs
44
16
16
12
• K • K •
3.42*
11.79*
3.07*
1.99*
1953
15+
Obs.
33 4
8 15
18 4
7 2
R.R.
.14*
.72*
.72*
.00
TABLE VI-11. OBSERVED DEATHS AND RELATIVE RISKS OF DEATH FROM
MALIGNANT NEOPLASMS, 1953-1970, FOR COKE PLANT WORKERS BY
WORK AREA AND LENGTH OF EMPLOYMENT THROUGH 1953
(adapted from Redmond et al. 1976)
Work Area
Total Coke Plant
Coke Oven
Oven Topside Full-time
Oven Topside Part-time
Oven Side Only
Nonoven
No One Coke Plant Area
Obs.
166
101
35
26
40
65
0
Years
5+
R.R.
1.47*
1.66*
3.70*
1.59t
1.17
1.28
— §
Employed Through
10+
Obs
136
85
22
31
32
» K • K •
1.50*
1.95*
5.12*
1.85*
1.46
48 1.10
3
— §
1953
15+
Obs.
108
63
12
32
19
39
6
R.R.
1.62*
2.40*
7.63*
2.73*
1.51
1.13
1.34
*Significant at P < 0.01.
tSignificant at P < 0.05.
§Less than five deaths.
88
-------
Redmond et al. (1979)--
The most recent update of mortality data on the coke plant workers cohort
(Lloyd and Ciocco 1969, Lloyd et al. 1970, Lloyd 1971, Redmond et al. 1972,
Redmond et al. 1976, and Mazumdar et al. 1975) extends the analysis through 1975
(Redmond et al. 1979). The vital status of the approximately 59,000
steelworkers in the Allegheny County study and the vital status of the
steelworkers in the ten non-Allegheny County steel plants were updated in order
to determine the expected cause-specific deaths. Work histories were not
updated because of lack of funding. Expected deaths and relative risk were
derived in the same manner as in the Redmond et al. (1972) study.
Among the coke oven workers in Allegheny County, excess mortality from
malignant neoplasms of the lung, trachea, and bronchus continued (Table VI-12).
As in earlier studies, this excess was significant (P < 0.01) among nonwhite
workers. Excess mortality of cancer of the kidney became significant (P < 0.05)
for white workers. Also, excess mortality from prostate cancer among total oven
workers became significant for the first time (20 observed, 12.74 expected,
P < 0.05). For workers ever having been employed at the coke ovens through
1953, excess mortality from all cancers; cancer of the lung, trachea, and
bronchus; kidney; and prostate is reported in Table VI-12. In addition to the
tumor sites listed in Table VI-12, the relative risk of mortality for "all other
cancers" for full-time topside workers was significantly (P < 0.05) elevated
(relative risk = 2.50). "All other cancers" include neoplasms other than of the
respiratory system, digestive organs and peritoneum, genitourinary organs,
buccal and pharyngeal organs, lymph and hematopoietic tissues, and skin. Among
coke oven workers employed for "five or more years through 1953," observed and
expected mortality and relative risk from all cancers and from cancer of the
lung, trachea, and bronchus; kidney; and prostate is reported in Table VI-13.
89
-------
TABLE VI-12. OBSERVED AND EXPECTED LUNG. TRACHEA, AND BRONCHUS; KIDNEY; AND PROSTATE CANCER DEATHS, 1953-75. AND
RELATIVE RISKS FOR ALLEGHENY COUNTY. PENNSYLVANIA STEELWORKERS EVER EMPLOYED AT THE COKE OVENS THROUGH 19b3 BY RACE AND PLACE OF EMPLOYMENT
(adapted from Redmond et al. 1979)
Cause of Death
Malignant Neoplasm
all sites
white
nonwhlte
Lung, Trachea,
and Bronchus
white
nonwhlte
Kidney
white
nonwhlte
Prostate
white
nonwhlte
Total
Coke Oven
Obs.
179
63
116
86
23
63
7
6
1
20
8
12
Exp.
144.38
62.47
81.91
47.43
19.02
28.41
2.61
1.20
1.41
12.74
4.13
8.62
R.R.
1.29*
1.01
1.55*
2.05*
1.22
2.87*
2.88t
5.42*
--§
1.67t
1.99
1.49
Oven
Topside
Place of Employment
Oven
Topside
Full-time
Obs.
56
4
52
35
2
33
2
1
1
4
0
4
Exp.
25.91
5.55
20.37
8.56
1.78
6.78
0.51
0.11
0.40
2.54
0.30
2.23
R.R.
2.37*
0.72
2.90*
4.87*
--§
6.17*
--§
--§
--§
~§
--§
--§
Part-time
Obs.
25
24
1
8
8
0
3
3
0
3
3
0
^xp.
21.86
20.97
0.89
6.84
6.58
0.25
0.40
0.38
0.02
1.41
1.29
0.12
R.R.
1.15
1.15
--§
1.17
1.22
~§
--§
--§
--§
"§
-§
"§
Side Oven
Obs.
98
35
63
43
13
30
2
2
0
13
5
8
Exp.
92.89
35.91
56.97
28.70
10.60
18.10
1.61
0.65
0.96
8.48
2.49
6.00
R.R.
1.06
0.97
1.13
1.58*
1.23
1.83*
"§
"§
"§
1.60
2.04
1.39
Obs.
115
94
21
28
26
2
1
1
0
9
4
5
Nonoven
Exp.
102.75
90.15
12.60
30.61
27.54
3.07
1.79
1.54
0.25
7.82
5.73
2.10
R.R.
1.13
1.05
1.76t
0.91
0.94
--§
-5
--§
--§
1.16
0.69
2.53
•Significant at P
tSlgniflcant at P < 0.05.
§Less than five deaths In both observed and expected; significance not calculated.
-------
TABLE VI-13. OBSERVED AND EXPECTED LUNG, TRACHEA. AND BRONCHUS; KIDNEY; AND PROSTATE CANCER MORTALITY, 1953-75,
AND RELATIVE RISKS FOR ALLEGHENY COUNTY, PENNSYLVANIA STEELWORKERS EMPLOYED FOR 5 YEARS OR MORE AT THE
COKE OVENS THROUGH 1953 BY RACE AND PLACE OF EMPLOYMENT
(adapted from Redmond et al. 1979)
Cause of Death
Obs
Malignant neoplasm
all sites 123
white 32
nonwhlte 91
Lung, Trachea, 63
and Bronchus
white 12
nonwhlte 51
Kidney 6
white 5
nonwhlte 1
Prostate 12
white 3
nonwhlte 9
*S1gn1fkant at P < 6.
^Significant at P < 0.
§Less than five deaths
Total
Coke Oven
. Exp.
89.02
32.70
56.32
28.30
10.02
18.28
1.83
0.64
1.19
8.73
2.25
6.48
01.
05.
In both
R.R.
1.46*
0.98
1.81*
2.63*
1.20
3.82*
3.55*
8.50*
--§
1.43
--§
1.47
observed
Obs.
37
2
35
25
2
23
0
0
0
3
0
3
Place
Oven
Topside
Full-time
Exp.
14.24
2.53
11.71
4.38
0.76
3.62
0.27
0.04
0.22
1.56
0.18
1.37
and expected;
R.R.
2.90*
--§
3.45*
6.94*
"§ '
8.10*
"§
"§
--§
"§
..§
"§
significance
Obs.
34
18
16
14
5
9
4
3
1
3
2
1
not
of Employment
Oven
Topside
Part-time
Exp.
24.05
16.31
7.74
7.50
5.23
2.27
0.52
0.32
0.20
1.83
0.98
0.85
ft. ft.
1.44t
1.11
2.18*
1.9H
0.96
4.38*
"§
--§
--§
"§
-§
--§
Side Oven
Obs.
52
12
40
24
5
19
2
2
0
6
1
5
Exp.
47.39
13.87
33.53
13.45
4.00
9.45
0.98
0.25
0.73
5.12
1.09
4.03
R.R.
1.11
0.86
1.22
1.91*
1.26
2.24*
"§
"§
--§
1.19
--§
1.27
Obs.
88
73
15
23
20
3
2
2
0
7
4
3
Nonoven
Exp.
71.54
62.70
8.83
20.84
18.83
2.00
1.28
1.09
0.19
5.94
4.42
1.51
R.R.
1.25
1.18
1.81t
1.11
1.06
--§
--§
--§
--§
1.19
--§
--§
calculated.
91
-------
For coke oven workers employed for "five or more years through 1953," the
relative risks of mortality from neoplasms of the lung, trachea, and bronchus,
as well as from kidney cancer, were higher than that for workers "ever employed
through 1953."
Among non-Allegheny County coke oven workers ever employed during 1951-55,
significant (P < 0.05) excess mortality from cancer of the lung, trachea, and
bronchus continued for both white and nonwhite workers. In addition, total
deaths from cancer at all sites was significantly in excess (194 observed,
162.56 expected, P < 0.01). Among nonwhites, a significant excess of prostate
cancer mortality (15 observed, 9.44 expected, P < 0.05) was found (Tables VI-14
and VI-15). These risks increased among workers employed for 5 years or more.
As in the Redmond et al. (1972) update, a dose-response was also evident by work
area. For workers employed for more than 5 years during 1951-55, the relative
risk of cancer of the lung, trachea, and bronchus was 3.47 (P < 0.01) for
full-time topside, 2.31 (P < 0.05) for mixed topside and side oven, and 2.06
(P < 0.05) for side oven experience. Kidney cancer mortality, which was
significantly (P < 0.05) elevated among the white Allegheny County workers, was
not significantly elevated among the non-Allegheny County workers. Cancer of
sites other than lung, trachea, and bronchus and prostate was not significantly
(P < 0.05) in excess; neither were causes of death other than cancer.
Among the 10 non-Allegheny County plants there was a considerable variation
from plant to plant in the relative risks for all causes, and one plant had
excessive risks for nearly every major cause of death. Although the amount of
risk for lung cancer varied among plants, there was a consistent pattern of the
number of observed deaths exceeding the number of expected deaths.
92
-------
TABLE VI-14. OBSERVED AND EXPECTED LUNG, TRACHEA, AND BRONCHUS; KIDNEY; AND PROSTATE CANCER
MORTALITY, 1951-1975, AND RELATIVE RISKS FOR NON-ALLEGHENY COUNTY STEELWORKERS EVER
EMPLOYED DURING 1951-1955, BY RACE AND PLACE OF EMPLOYMENT
(adapted from Redmond et al. 1979)
Cause of Death
Malignant Neoplasm
All sites
White
Nonwhite
Lung, Ti achea, and
Bronchus
White
Nonwhite
Kidney
White
Nonwhite
Prostate
White
Nonwhite
Total Coke
Oven
Obs.
194
63
131
82
28
54
5
2
3
17
2
15
Exp.
162.56
56.92
105.64
53.66
18.64
35.02
4.13
1.40
2.73
12.23
2.79
9.44
R.R.
1.36*
1.18
1.47*
2.20*
2.16*
2.23*
1.36
— -§
— -§
1.81
-— §
2.45t
Place of Employment
Oven Topside Oven Topside
Full-time Part-time
Obs.
71
12
59
39
6
33
1
0
1
5
0
5
Exp.
45.56
10.82
34.75
16.23
3.41
12.82
0.95
0.14
0.81
2.94
0.44
2.50
R.R.
1.79*
1.13
2.04*
3.52*
2.15
3.98*
— - §
— - §
-— §
1.94
— -§
2.43
Obs.
14
12
2
8
7
1
1
1
0
0
0
0
Exp.
18.34
13.76
4.58
4.76
3.90
0.86
0.47
0.32
0.15
0.68
0.59
0.18
R.R.
0.69
0.83
— -§
1.96
2.22
— -§
— - §
— -§
— -§
-— §
— -§
-— §
Side Oven
Obs.
109
39
70
35
15
20
3
1
2
12
2
10
Exp.
92.30
31.70
60.60
25.99
9.37
16.62
2.51
0.71
1.80
7.75
2.19
5.56
R.R.
1.28t
1.35
1.24
1.55
2.07
1.30
— -§
— -§
-— §
2.03
-— §
2.65t
*Significant at P < 0.01.
tSignificant at P < 0.05.
§Less than five deaths (observed and expected),
93
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TABLE VI-15. OBSERVED AND EXPECTED LUNG, TRACHEA, AND BRONCHUS; KIDNEY; AND PROSTATE CANCER
MORTALITY, 1951-1975, AND RELATIVE RISKS FOR NON-ALLEGHENY COUNTY STEELWORKERS EMPLOYED
FOR 5 OR MORE YEARS AT TIME OF ENTRY TO STUDY BY RACE AND PLACE OF EMPLOYMENT
(adapted from Redmond et al. 1979)
Cause of Death
Malignant Neoplasm
All sites
White
Nonwhite
Lung, Trachea, and
Bronchus
White
Nonwhite
Kidney
White
Nonwhite
Prostate
White
Nonwhite
Total Coke
Oven
Obs.
118
33
85
50
14
36
3
2
1
13
1
12
Exp.
96.04
29.25
66.79
31.75
9.42
22.33
2.73
0.98
1.74
7.92
1.38
6.54
R.R.*
1.45t
1.23
1.57t
2.49t
2.15
2.66t
11
11
1!
2.63§
11
3.59§
Place of Employment
Oven Topside Oven Topside
Full-time Part-time
Obs.
42
1
41
19
0
19
0
0
0
6
0
6
Exp.
26.03
1.78
24.25
8.51
0.57
7.94
0.63
0.00
0.63
2.39
0.16
2.23
R.R.*
1.99T
11
2.16t
3.47t
11
4.00t
11
11
11
3.71§
11
4.21§
Obs.
27
14
13
13
6
7
1
1
0
2
0
2
Exp.
24.92
13.74
11.18
6.87
3.86
3.01
0.79
0.38
0.42
1.41
0.65
0.76
R.R.*
1.11
1.03
1.20
2.31§
1.83
2.90§
11
11
1!
11
11
11
Obs.
49
18
31
18
8
10
2
1
1
5
1
4
Side Oven
Exp.
39.61
13.50
26.11
11.23
4.06
7.16
1.33
0.39
0.94
2.75
0.79
1.96
R.R.*
1.35
1.54
1.27
2.06§
3.48§
1.59
11
11
11
2.40
11
11
*Relative risks that are statistically significant were not indicated in Redmond et al. (1979). These were obtained by
personal communication with Redmond (1981).
tSignificant at P < 0.01.
§Significant at P < 0.05.
IILess than five deaths (observed and expected).
94
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British Studies
Reid and Buck (1956) —
Reid and Buck (1956) studied the causes of death of men dying while "on the
books" of the British National Coal Board coking plants during the period
1949-54. This included both retired and actively employed workers. Causes of
death were ascertained through the funeral fund of the National Union of
Mineworkers or through a vital statistics search of the General Register Office.
The authors analyzed mortality for the currently employed and retired workers
separately.
For the actively employed, information on age and job distribution was
obtained from a special census taken in 1952. Additional information on the
nature and duration of different jobs held in the plants was obtained from a
sample of 10% of the workers. Total man-years of exposure over the period
1949-54 were divided proportionally according to the age and job distributions
found in the 1952 special census. Expected deaths were derived by multiplying
the accumulated man-years in each age and job category by the comparable cause
and age-specific death rates derived from a "large industrial organization"
during the period 1950-54. Although the authors did not disclose the identity
of this large industrial organization, they do state that the derived death
rates for this industry were similar to those of civil servants of the General
Post Office, 60 years of age or younger, during the same period. Data on civil
servants were not available beyond the usual retiring age of 60.
The coking plant workers generally fell into four main groups. The first
group consisted of men involved in operating the coking ovens, driving the ram,
filling the oven, clearing the hydraulic main, etc. The second group was
involved in the recovery of by-products such as tar, ammonia, and benzole. The
95
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third group was composed of laborers whose duties and contacts with the
processes varied greatly. The fourth group included maintenance men and
craftsmen who occasionally were in contact with the processes. The number of
workers falling into each of these four job groups was not reported. Mortality
by cause and occupational exposure is reported in Table VI-16.
There was a significant difference between observed and expected mortality
for all other cancer combined (minus respiratory cancer) for coke workers (24
observed vs. 16 expected; P < 0.05, two-tailed test). For respiratory cancer,
however, there was no increase in observed mortality over that expected. If the
occupational classifications are divided* according to whether the men were ever
employed at any time as oven workers or never employed as oven workers, oven
workers would have a significantly elevated risk from cancers at all sites (40
observed vs. 32 expected; P < 0.05, one-tailed test) and an elevated risk (14
observed vs. 10 expected) of respiratory cancer, which is not statistically
significant. A significant excess risk of death (except respiratory cancer) is
apparent in men who never worked at the coke oven (205 observed vs. 162
expected; P < 0.01, one-tailed test). Men employed at any time as by-product
workers do not appear to be subject to an excess risk of respiratory cancer,
"cancer all sites combined" or "deaths all causes combined except respiratory
cancer." By contrast, men who were never by-product workers have a
significantly elevated risk of death excluding respiratory cancer (254 observed
vs. 218 expected; P < 0.01, one-tailed test).
Twenty workers who died from lung cancer while still on the company payroll,
and for whom detailed occupational histories were available, spent an average of
*This division was proportionally distributed according to the work
histories of the 10% random sample (800 workers).
96
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TABLE VI-16. MORTALITY* IN COKING PLANT WORKERS ACCORDING TO OCCUPATIONAL EXPOSURE
(adapted from Reid and Buck 1956)
Mortality by Last Job Held Mortality by Work History
Men Never Men Employed Men Never
Men Employed Employed at Any Time Employed as
Oven By-product Maintenance at Any Time as as Coke Oven as By-product By-product
Workers Workers Workers Oven Workers Workers Workers Workers
OEOEOEOE OE OE
Respiratory
cancer 4 5 3 3 14 14 14 10 7 13 4 6
All cancerst 24§ 16 9 9 38 48 40V 32 31 41 16 18
Other causes 50 49 29 26 166 141 71 95 174 121 46 53
Total
excluding
respiratory
cancer 74 65 38 35 204 189 111 127 20511 162 62 71
0 E
17 17
55 55
199 163
254 218
*0 = observed deaths, E = expected deaths (adjusted for age) based on an unspecified industry for the
period 1949-1954.
t"All cancers" was probably meant to be reported by Reid and Buck as "all other cancers." Otherwise the
number for the "total excluding respiratory cancer" is in error.
§Significantly in excess of expected (P < 0.05, two-tailed test).
HSignificantly in excess of expected (P < 0.05, one-tailed test).
97
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23.0 years in the coking plants and 16.3 as coke oven workers. These figures
are not appreciably different from the average duration of employment for men of
the same age included in the random sample of 800 (25.3 years in the coking
plants and 16.7 years as oven workers). Comparison of "average" employment
duration may not reflect differences in length of employment between the lung
cancer cases and the total random group, however. It is possible that a number
of older workers in either group may have worked for only a short period of time
which might bias any comparison of averages.
The number of retired workers was not known; only the number of retirees who
died was known. Therefore, for retired workers, the proportion of respiratory
cancer deaths to all cancer deaths and the proportion of all cancer deaths to
total deaths were compared among occupational groups (oven workers, by-product
workers, laborers, maintenance workers, and foremen) by last job worked. They
were also compared by whether or not they had ever worked as oven workers and
whether or not they had ever worked as by-product workers. No differences were
found by either comparison. Since the ages of death of the retired workers were
not known, mortality was not compared by age.
The authors reported a significant (P < 0.05, one-tailed test) excess in
other than respiratory cancer mortality for workers whose last job was at the
coke ovens. No excess in respiratory cancer was seen however. For workers who
had ever worked at the coke ovens, there was no significant (P < 0.05) increase
in either respiratory or other cancer. For retired workers, no difference was
seen in the proportions of cancer deaths. The amount of confidence that can be
placed in the validity of the results of this study is in question, however,
because of the superficiality and lack of details in the description given by
the author regarding the methodology and conduct of the study. The authors fail
to adequately define the basic study population. It is unclear whether the
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study population includes all men who ever had a record of employment in the
coke plant during the period 1949-54, since the author refers to an "average" of
8,000 men employed in National Coke Board (NCB) coking plants or just those
found through the special 1952 census. If the cohort consisted of workers
employed in 1952, and since there was little or no follow-up of any of these
members, it appears that this study is little more than a cross-sectional study
of mortality in a conglomerate of several different coke plants. As much as can
be determined, the observed deaths are only those deaths of members of the study
group who were employed in the period 1949-54. Also, it should be noted that
the number of lung cancer deaths observed may have been deficient since only men
dying while "on the books" of the coking plants during the period 1949 to 1954
were included. Lloyd (1971) reported (apparently from communication with Reid
and Buck) that men were removed from the books after prolonged absence from
work.
Since follow-up after 1954 was nonexistent, latent effects were not
adequately considered. Furthermore, the death rates utilized in calculating
expected deaths were those prevailing in an unknown "large industrial
organization." It is not known how they were derived or defined. Therefore, it
cannot be said with any certainty that they are compatible with whatever
definition the authors utilized to derive the study population. Regarding the
retired workers, comparison of proportionate mortality without any
age-adjustment must be viewed with some skepticism. In short, this study leaves
many unanswered questions and is so ambivalent that it is difficult to place any
confidence in the study results.
Davies (1977, 1978)--
Davies (1977, 1978) reported on the mortality experience from May 1954 until
99
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June 1965 of 610 coke oven workers at two South Wales coke works (Works A and
B). The 610 workers employed at the two plants had 6261.5 man-years of
follow-up; eighty-eight had died during the follow-up period. Male mortality
rates for England and Wales (average for 4 years, 1958-61) were multiplied times
the person-years of follow-up in each age category to obtain the expected deaths
for the coke workers. Observed and expected deaths were for total mortality
from malignant neoplasms of different sites, cardiovascular mortality,
respiratory disease mortality, and mortality from other causes. The Standard
Mortality Ratio for the two coke works was 92. There was no significant
(P < 0.05) excess in mortality for any of the diseases evaluated including
cancer of the lung (8 observed vs. 8.94 expected), cancer of the bladder and
kidney (3 observed vs. 1.9 expected), and respiratory disease (14 observed vs.
12.6 expected). There was a significant (P < 0.05, one-tailed test) negative
difference between the observed and expected deaths from cardiovascular disease
(29 observed vs. 41.36 expected).
The follow-up period as reported in this study was 11 years (1954-1965).
The follow-up period would have been longer, of course, for those workers who
started work before 1954. Without further information, however, the follow-up
period in the Davies study may not be considered adequate to detect differences
in lung cancer mortality since the latency period from exposure to the start of
lung cancer may be as long as 20 to 30 years.
Davies did not describe the degree of environmental exposure of the coke
workers (e.g., topside of ovens, side of ovens, nonovens) as has been done in
other studies (Lloyd 1971, Redmond et al. 1972, Redmond et al. 1976, Redmond et
al. 1979). Extremely high risk has been found to be limited to a small
proportion of the coke oven population. A comparison of coke oven workers to
non-coke oven workers, without any further delineation, may not be able to
detect differences in lung cancer risk.
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Collings (1978)--
Collings (1978) conducted a follow-up study of 2,854 male coke workers
employed in 14 coke works scattered throughout Great Britain. To be included in
the study, these workers had to have attained a minimum of 1.5 years continuous
employment at the plant ending in July 1967. They were subsequently followed 9
years from August 1, 1967 to August 1976 and their mortality experience was
tabulated. The cohort was derived from lists provided by the coke works. For
each person in the cohort, a questionnaire was submitted to the respective coke
works asking personal information, work since joining the coke industry, and
work prior to date of entry; completion of the questionnaire was arranged by a
senior medical officer familiar with the works. Three distinct occupational
groups, nonovens, part-ovens, and ovens were designated. The "nonovens"
category included 392 men who had no contact with the ovens. "Part-ovens"
included 742 men with some occasional contact with oven work. "Ovens" was
comprised of 1,615 men who had at least one specialized oven job prior to August
1, 1967. Length of employment was tabulated for the "ovens" group but not for
the other groups.
For comparison, expected deaths were derived in two separate ways. In the
first method, the mortality experience of men in the study cohort was compared
to that of all men in Great Britain. Person-years at risk were accumulated in
the appropriate age, calendar-time period, cancer latency period, and
occupational groups. Standard population death rates were applied to the
comparable person-years categories to derive expected deaths and finally
Standard Mortality Ratios (SMRs). In the second method, the author derived a
"comparative mortality figure" (CMF) for each occupational category (ovens,
nonovens, and part-ovens). The CMF was derived as the ratio of the sum of the
observed mortality across all age categories to that of the sum of the expected
mortality.
101
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Expected mortality was derived in the following manner:
Number in age
group of
occupational
category
Number of deaths for the
particular cause in the
age group of the occupa-
tional category
Number in age
group for all
occupational
categories
Number of deaths for the
particular cause in the
age group of the occupa-
tional category
All deaths for the
x particular cause
in the age group
= Expected deaths for the occupational
category by age group.
With regard to latency and specific job within the coke works, only lung
cancer mortality appears to be somewhat excessive but not significant when
contrasted with rates in Great Britain (45.0 observed vs. 35.7 expected, P =
0.12). If only the coke oven workers in England and Wales (not Scotland) are
considered and population mortality data from those two countries are used to
derive expected deaths, then lung cancer mortality is significantly elevated (41
observed vs. 32.4 expected mortality, P < 0.05). However, lung cancer mortality
is not significant when manually-skilled (40.8 expected), partly-skilled (39.5
expected), or unskilled (44.5 expected) workers in England and Wales are used to
derive expected lung cancer deaths. The author notes that most workers in the
study cohort would be considered partly-skilled and the lung cancer mortality in
that group is almost identical to that of the partly-skilled in England and
Wales. However, overall mortality is 17% lower (254 observed vs. 306.4
expected) compared to partly-skilled workers. This observation led the author
to comment that the high proportion of lung cancers in the study cohort may be
related to occupational factors.
A smoking history questionnaire was submitted to a limited subgroup of
study members who were still employed at the works during data collections (1973
to 1975), and who attended the works medical center at that time. This
102
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represented only 41% of the workforce. Based on such limited data, the author
concluded that the 26.7% excess lung cancer mortality could not be due to
excessive tobacco consumption on the part of members of the study population.
Cigarette consumption in 4 of 14 coke works was, according to the author, "above
average," while in the remainder it was below average.
With respect to the three occupational groups, i.e., ovens, part-ovens, and
nonovens, the comparative mortality figure computed for each occupational group
for certain selected causes, including lung cancer, revealed no statistically
significant excesses. However, the author reports that when SMRs were
calculated for the same occupational groups (utilizing the male population of
Great Britain), lung cancer was excessive in all three groups, but no tabular
data is provided to support this assertion.
The risk of lung cancer as well as the risk of all malignant neoplasms
apparently increases with increasing lengths of employment on the coke ovens,
although not significantly so. The population of employees who had worked on
the ovens for more than 10 years had an SMR of 127 and a CMF of 1.24 based on 17
observed lung cancers. Additionally, the SMR and CMF for the cause "all
malignant neoplasms" was 126 and 1.30, respectively, based upon 30 observed
cancer deaths in the same workers. Had the author looked at latency and length
of employment together, the contribution of both to the increase in risk may
have been better defined.
The findings above, the author concludes, tend to support American studies
that show an excessive risk of lung cancer in coke workers, although overall
mortality in general is "favorable." The fact that none of the findings are
statistically significant may be a consequence of the short 9-year period of
observation.
103
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Another 6 to 10 years of observation may be needed before a statistically
significant excess risk of lung cancer is found. Secondly, the author did not
differentiate between topside and side oven workers. The earlier American
studies have pinpointed the highest risk mainly to topside workers. Thirdly, to
measure the impact of length of employment on risk in coke ovens work is
meaningless unless latent factors are considered simultaneously. What the
author perceives as a correlation of length of exposure to risk may well be only
a veiled manifestation of a latent effect.
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Sakabe et al. 1975 --
Sakabe et al. (1975) studied lung cancer mortality and cancer mortality (all
sites) for the years 1949-1973* among retired coke oven workers from 11
companies in Japan. At the time of the study there were 36 companies producing
coke in Japan. No explanation was provided as to why the other companies did
not participate in the study. Mortality was ascertained by a questionnaire to
the industrial physician or chief health inspector of each industry. The
expected mortality was calculated from the vital statistics for the general
Japanese male population for the corresponding period of time. Coke ovens in
Japan are categorized as those for blast furnace coke, those for casting coke,
and those for general coke, depending on the purpose for which the coke is
manufactured. The furnace temperature of coke ovens is about 1300°C for blast
furnace coke, 1000°C for casting coke, and 1200°C for general coke.
The 11 companies surveyed included four iron and steel plants, four city gas
companies, and three "coke manufacturing chemical companies and coke
manufacturing companies." Coke ovens in the iron and steel plants in Japan are
used solely for manufacturing blast furnace coke, and coke ovens of city gas
plants are used for manufacturing coke for blast furnaces, casting furnaces, and
general use. No description of the purpose of the coke production was given for
the three "coke manufacturing chemical companies and coke manufacturing
companies." There was no statistical difference between the observed and
expected cancer (all sites) mortality or lung cancer mortality when the study
population consisted of retired workers from all 11 companies combined.
Sakabe et al. then compared the observed cancer mortality for the 674
retired workers from the four iron and steel plants and the 1,261 retired
*Altnough 2,201 workers who retired between 1947 and 1973 were traced, only
the cancer deaths from 1949 to 1973 were included in the study. The authors
provided no explanation for the period 1947 to 1949.
105
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workers at the four city gas companies with the expected cancer mortality for
those companies. The number of retired workers among the "coke manufacturing
chemical companies and coke manufacturing specialized companies" was too small
for statistical comparison of observed and expected cancer mortality. Cancer
mortality (all sites) was not significantly (P < 0.05) different from that
expected for either the iron and steel plants (36 observed, 31.87 expected) or
the city gas companies (51 observed, 69.77 expected). Lung cancer mortality
among the iron and steel plants coking companies was significantly greater than
expected however (8 observed, 3.38 expected, P ^ 0.022). No statistical
difference between the observed and expected lung cancer mortality was found for
the city gas companies.
When Sakabe et al. looked at proportionate cancer mortality, the proportion
of lung cancer cases to all cancers was significantly greater (P $ 0.05)
than expected for the iron and steel plants but not for the city gas companies.
Sakabe et al. also studied the age of lung cancer onset and working period
at the coke ovens. For all coke oven (including both city gas and iron and
steel plants) workers, lung cancer was found to occur after 5 years of working
and at the age of 50 or over (except for one individual whose age was reported
as 44). Anong coke oven workers of the iron and steel plants, lung cancer
occurred after 10 years of working and at the age of over 50 years.
Smoking data for the lung cancer cases was incomplete. Of the 18 coke oven
workers who died from lung cancer, 10 were smokers, 2 were nonsmokers, and no
information was available for 6. Reliable information concerning the amount of
smoking for each smoker could not be obtained.
In conclusion, Sakabe et al. found a statistically significant
(P ^ 0.022) excess of lung cancer mortality among workers retired from
plants that produce coke for blast furnaces, but not among retired coke oven
106
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workers from city gas companies. The strength of this association is weakened,
however, by the lack of adequate smoking data. An excess of lung cancer
mortality among the coke oven workers at the city gas companies was not found
perhaps because the coke ovens at the gas companies may be operated from 100°C
to 300°C lower than the coke ovens at the iron and steel plants.
The authors also found that the proportion of lung cancer mortality to all
cancer mortality was significantly (P < 0.05) in excess among retired coke oven
workers of iron and steel plants, but not among retired coke oven workers of
city gas industries.
107
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Summary
Lloyd (1971) and Redmond et al. (1972, 1976, 1979) found an excess of total
cancer mortality and respiratory organ cancer mortality among workers employed
at coke works. Both were found to be dose-related. Workers exposed to low
(side oven), medium (side oven and topside), and high (topside only) exposure
had increasingly greater excesses of total cancer mortality rates and lung
cancer mortality rates. Not only was there an increase in excess lung cancer
mortality by occupation site, but there was an increase by length of exposure
as well. Workers exposed 5 years or more had a greater excess of lung cancer
than workers exposed less than 5 years.
As indicated earlier, one criticism of the Lloyd (1971) and Redmond et al.
(1972, 1976, 1979) studies is that smoking data were not taken. An analysis
of lung cancer mortality is generally not considered adequate without smoking
data. However, the dose-responses seen in the Lloyd and Redmond et al.
studies is so striking that it is improbable that the excess in lung cancer
mortality could be explained by differences in smoking habits.
An apparent discrepancy in the Lloyd and Redmond et al. studies is that
the excess lung cancer mortality among nonwhite workers in Allegheny County
was significant while that among white workers was not significant. Several
explanations have been offered for this phenomenon. Perhaps the most obvious
explanation is that more nonwhites than whites were employed at the coke ovens
in Allegheny County, particularly as full-time topside workers, and the excess
among nonwhites may have been significant because of their larger sample size.
Redmond et al. (1979) suggested that the difference may be because, within the
respective subsites at the coke ovens, whites and nonwhites may have had
different jobs and consequently different exposure to volatile hydrocarbon
effluents. Redmond et al. (1979) also suggested that the difference may be
108
-------
because mortality rates for lung cancer have been shown in other studies to be
inversely correlated with educational qualifications and occupational
category. As Redmond et al. (1979) noted, however, the expanded studies of
non-Allegheny County coke oven workers found that the lung cancer risk was
significant for both whites and nonwhites. In addition, Mancuso (1977) has
suggested that the difference in cancer mortality risk between the nonwhites
and whites in the Allegheny County plants may have resulted because a majority
of the nonwhites were migrants from the South.* Since Mancuso did not report
how many of the total steelworker population (from which the expected
mortality data were derived) were also migrants from the South, it would be
premature to conclude that being a nonwhite worker from the South predisposes
one to cancer. Also, it would be difficult to separate the effects of place
of origin and race from the effects of industrial exposure. Impoverished
migrant workers may well take any job that is offered including those jobs
that place persons at an excess risk of cancer. Finally, as noted above, the
Redmond et al. studies of non-Allegheny County coke oven workers found that
excess risk of lung cancer was significant for both whites and nonwhites.
Prostate cancer mortality was significantly (P < 0.05) increased among
all Allegheny County coke oven workers ever employed in 1953. For workers
having worked 5 or more years, however, the excess was not significant.
Similar to the apparent discrepancy between whites and nonwhites above, an
excess of prostate cancer mortality did exist among workers employed 5 years
or more, but possibly because of small sample size, the excess was not
significant. Among the non-Allegheny County workers, the excess in
*In 1974, Mancuso and Sterling reported that migrants in Ohio,
particularly migrants from the South, had higher death rates for various
cancer sites than did persons born in Ohio.
109
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prostate cancer was significant for nonwhite workers only.
Kidney cancer mortality was significantly increased (P < 0.01) among white
workers in the Allegheny County study. Small excesses in kidney cancer were
seen for both whites and nonwhites in the non-Allegheny County plants, but
these excesses were not significant (P < 0.05).
Sakabe et al. (1975) found that there was a significant excess of lung
cancer mortality among retired Japanese coke oven workers at iron and steel
coking plants when compared to cancer mortality among the general population.
Sakabe et al. did not divide the retired workers into exposure categories as
had been done in the American studies. Coke oven workers from the low
exposure groups would have been mixed with persons from high exposure groups.
It is likely that persons in the high exposure groups would have been at an
even greater lung cancer risk. A lack of smoking data, however, weakens the
findings of the study.
Reid and Buck (1956) found a significant (P < 0.05, one-tailed test)
difference between the observed and expected mortality for cancer, other than
respiratory cancer, for coke plant workers whose last job was listed as "coke
ovens." No excess was found for respiratory cancer deaths. When mortality
was analyzed by whether the workers had ever worked at the coke ovens, no
significant excess in respiratory or other cancer mortality was found. The
Reid and Buck study had a number of deficiencies, however. The study
population was poorly defined and the "observed deaths" may not have included
deaths of workers "not on the books." Furthermore, the study did not
sufficiently address the issue of a cancer latency period since little or no
follow-up of vital status occurred. Analysis of mortality among retired
workers was not adequate since there was no adjustment for age.
Davies (1977, 1978) did not find any significant difference between the
110
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observed and expected cancer mortality of the coke oven workers at two coke
works in South Wales. Davies followed his cohort for only 11 years, however.
Also, Davies did not consider the degree of environmental exposure among the
coke oven workers. Extremely high risk has been found to be limited to only a
small proportion of the coke oven population. The comparison of coke oven to
non-coke oven workers may not have been able to detect any differences
especially considering the relatively short follow-up period.
Coll ings (1978) found an excess of lung cancer among the coke oven workers
when compared to rates for Great Britain (45.0 observed vs. 35.7 expected);
this excess was not significant (P < 0.05), however. Like the Davies study,
Ceilings followed his cohort for a relatively short period of time (9 years).
Also, similar to Davies, the author did not evaluate the degree of
environmental exposure of the coke workers (i.e., he failed to differentiate
between topside and side oven workers). It should also be noted that coke
ovens are operated at lower temperatures in Great Britain than they are in the
United States (Doherty and DeCarlo 1967), which may contribute to the lack of
positive findings in the three British studies on coke workers (Reid and Buck
1956, Davies 1977, and Ceilings 1978).
The update by Redmond et al. of the study begun by Lloyd consistently
showed a significant excess of lung, trachea, and bronchus cancer mortality.
In the Redmond et al. studies, there was a dose-response both by working area
(topside, side oven and part-time topside, and side oven) and by length of
exposure. Prostate cancer and kidney cancer also appeared to be in excess in
the Redmond et al. (1979) update. Because the British studies did not follow
the workers as long as the American studies did, and because neither the
British studies nor the Sakabe et al. study considered occupational categories
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within the coke works, the positive results of the American studies are
considered a better evaluation of the cancer risk to coke oven workers.
Therefore, based on results of the American studies, it is concluded that
exposure to coke oven emissions increases the risk of cancer of the lung,
trachea, and bronchus; kidney; and prostate, as well as cancer at all sites
combined.
112
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ANIMAL STUDIES
Topside Coke Oven and Coke Oven Main
Topside coke oven sample extract has been tested as a tumor initiator in
initiation-promotion skin treatment studies in two strains of mice (Nesnow et
al. 1981, Nesnow 1980). An extract of material from a coke oven collecting
main has also been evaluated for activities as a whole carcinogen, an
initiator, and a promoter [in skin treatment studies with one strain of mouse.
(Nesnow et al. 1981)].
Initiation-Promotion Studies—
Nesnow et al. (1981) have evaluated the effects of extracts of topside
coke oven emission and coke oven main samples in initiation-promotion and
complete carcinogenicity studies in mice. The methods for obtaining the test
samples from coke ovens has been described by Huisingh (1981) and Huisingh et
al. (1979). Topside coke oven samples were collected as particulate matter
with a Massive Air Volume Sampler, and coke oven main samples were obtained
from a separator located between the gas collector and the primary coolers
within the coke oven battery. The samples were soxhlet-extracted with
dichloromethane, which was subsequently removed by evaporation under dry
nitrogen gas. All test materials used in this study were prepared under
yellow light immediately before application, in 0.2 ml spectral grade acetone,
onto test sites.
Mice of the SENCAR strain, derived from mating female Charles River CD-I
mice with male skin tumor sensitive (STS) mice, were selected as the test
animals in this study.
Each control and treatment group consisted of 40 male and 40 female mice
which were 7 to 9 weeks old at the start of the study. Animals were caged in
113
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groups of 10 under yellow light. Test sites on the skin were shaved 2 days
before initial treatment, and only mice in the resting phase of the hair cycle
were used. In the initiation-promotion experiments, initiating agents were
applied as single doses except for the 10 mg (highest) dose which was given as
five daily doses of 2 mg each. At 1 week following application of initiator,
2 ug of the promoter 7,12-dimethylbenz[a]anthracene-12-0-tetradecanoylphorbol-
13-acetate (TPA) was topically applied twice per week. In tests for complete
carcinogenicity, test material was applied once weekly, or twice weekly at the
highest dose, for 50 to 52 weeks. Test substances evaluated as promoting
agents were applied to the skin once each week, or twice each week at the
highest dose, for 34 weeks following skin treatment with a 50.5 ug dose of the
initiator benzo[a]pyrene (B[a]P).
Animals were observed weekly for tumor formation, and papillomas over 2 mm
in diameter and carcinomas were included in cumulative totals if they
persisted for at least 1 week. Papillomas were scored at 6 months or, in the
test for promoting activity, 34 weeks, and carcinomas were totaled after 1
year. The authors indicate that examination of animals by necropsy and
tissues and tumors by histopathology was being done and that pathologic data
would be presented in a separate forthcoming report.
Results of initiation-promotion experiments on topside coke oven sample
extract, coke oven main sample extract, and B[a]P as initiating agents are
compared in Table VI-17. The stronger effect of the coke oven main sample
compared to the topside coke oven sample reflects the greater concentration of
ingredients contributing to the initiating activity of the former sample.
Responses to the coke oven main sample and B[a]P in the study for complete
carcinogenesis are shown in Table VI-18. Promoting activity was found with
the coke oven main sample and TPA following initiation with B[a]P
114
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TABLE VI-17. SENCAR MOUSE SKIN TUMORIGENESIS
(Nesnow et al. 1981)
Dose
(ug/mouse)
Mice with Mice with
No. Mice Papillomas* Papillomas Carcinomast Carcinomas
Surviving (%) per mouse* (%) per Mouset
BENZO[A]PYRENE - TUMOR INITIATION
0
0
2.52
2.52
12.6
12.6
50.5
50.5
101
101
100
100
500
500
1000
1000
2000
2000
10,000
10,000
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
37
39
40
39
40
37
39
40
38
38
40
40
40
40
37
39
39
38
39
40
8
5
45
31
73
57
100
75
95
97
TOPSIDE COKE
13
10
73
70
95
72
95
90
100
100
0.08
0.05
0.50
0.44
1.8
1.1
5.8
2.8
10.2
7.9
OVEN - TUMOR INITIATION
0.13
0.20
1.6
1.8
2.6
2.0
4.0
3.5
7.1
7.7
5
0
5
5
20
23
25
20
30
25
0
8
5
15
15
3
13
10
13
20
0.05
0
0.07
0.05
0.20
0.23
0.25
0.20
0.33
0.25
0
0.08
0.05
0.15
0.15
0.03
0.13
0.10
0.15
0.23
COKE OVEN MAIN - TUMOR INITIATION
100
100
500
500
1000
1000
2000
2000
10,000
10,000
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
38
39
39
39
39
39
40
40
38
37
50
31
90
82
87
90
78
100
100
100
0.63
0.38
3.7
2.2
3.3
3.1
3.1
5.3
8.9
8.1
10
25
54
54
53
48
48
45
55
65
0.10
0.25
0.59
0.54
0.53
0.48
0.48
0.45
0.55
0.65
tCumulative score after one year.
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TABLE VI-18. SENCAR MOUSE SKIN TUMORIGENESIS
(adapted from Nesnow et al. 1981)
Dose Mice with Carcinomas*
(ug/mouse/week) (%)
12.6
12.6
25.2
25.2
50.5
50.5
101
101
202
202
0
0
100
100
500
500
1000
1000
2000
2000
4000
4000
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
(M)
(F)
BENZO[A]PYRENE - COMPLETE CARCIMOGENESIS
10
8
63
43
93
98
80
90
80
93
0
0
COKE OVEN MAIN - COMPLETE CARCINOGENESIS
5
5
36
30
48
60
82
78
98
75
Carcinomas
per Mouse*
0.10
0.08
0.63
0.43
0.93
0.98
0.83
0.98
0.80
0.98
0
0
0.05
0.05
0.36
0.30
0.55
0.60
1.00
0.78
0.98
0.85
^Cumulative score after one year.
116
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(Table VI-19). Spontaneous tumor formation in the control groups was not
evident in the studies for complete carcinogenesis and promoting activity
(Tables VI-18 and VI-19) and was below 10% incidence for papillomas and was 5%
(males) or 0% (females) incidence for carcinomas in the experiment for
initiating activity (Table VI-17).
Results of the study by Nesnow et al. (1981) show that coke oven main
sample extract contained ingredients capable of producing skin tumors in
SENCAR mice either as an initiator, a promoter, or a complete carcinogen.
Topside coke oven sample extract was also active as an initiating agent;
however, according to Nesnow et al. (1981), an unknown portion of the topside
sample was contaminated with particulate matter from ambient air due to the
location of the Massive Air Volume Sampler and local wind conditions (this
issue is further discussed on pages 39, 41, and 44 of the mutagenicity section
herein). Hence, the extent to which the topside coke oven sample extract used
in the initiation-promotion experiment is representative of topside coke oven
sample per se appears uncertain.
Data in Tables VI-17 and VI-18 show that the tumorigenic responses to the
coke oven sample extracts and B[a]P tended to be constant at all doses above
the lowest dose in the dose ranges used. The nature of these dose-responses
indicates that the doses used were in the range capable of producing maximal
effects in relation to the sensitivity of the SENCAR strain to the initiating
and complete carcinogenic properties of these test materials. The authors
proposed that a lack of a monotonic dose-response across a dose range may be
due to a toxic effect of the test material being tested which damages the
epidermis to yield a reduced tumorigenic response. Forthcoming results of the
histopathologic examination of skin test sites may provide evidence in favor
of this possibility. However, although not identified as an experimental
117
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TABLE VI-19. SENCAR MOUSE SKIN TUMORIGENESIS
COKE OVEN MAIN - TUMOR PROMOTION
(adapted from Nesnow et al. 1981)
TPA
TPA
Dose
(ug/mouse)
0 (M)t
0 (F)
100 (M)§
100 (F)
500 (M)
500 (F)
1000 (M)
1000 (F)
2000 (M)
2000 (F)
4000 (M)1I
4000 (F)
, 4 ug (M)#
, 4 ug (F)
Mice with Papillomas*
0
0
3
10
26
38
53
68
84
85
100
100
86
97
Papillomas per mouse*
0
0
0.02
0.10
0.44
0.83
1.2
1.2
2.5
3.1
8.2
8.8
3.1
5.9
*Scored at 34 weeks.
tMice initiated with 50.5 ug benzo[a]pyrene (B[a]P) and subsequently
treated weekly with acetone.
§Mice initiated with 50.5 ug (B[a]P) and subsequently treated weekly with
coke oven main.
IIMice initiated with 50.5 ug (B[a]P) and subsequently treated twice weekly
with 2 mg coke oven main.
#Mice initiated with 50.5 ug (B[a]P) and subsequently treated twice weekly
with 2 ug TPA.
118
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problem in the study report, it is possible that the rather constant response
over the dose ranges used may be due to incomplete solubility of the test
samples in acetone, which in turn actually might have resulted in the
application of rather similar doses throughout the dose ranges. Nonetheless,
although the responses in Tables VI-17 and VI-18 were generally not monotonic
throughout the entire dose ranges used, the data clearly show positive
activity for the indicated test materials. As shown in Table VI-19, a clearer
indication of a dose-related effect was obtained in the evaluation of coke
oven main sample extract as a promoter.
In summary, coke oven main sample extract was positive as a complete
carcinogen, an initiator, and a promoter on the skin of SENCAR mice, and
topside coke oven sample extract was positive as an initiator on the skin of
SENCAR mice.
Nesnow (1980) reported results of an additional initiation-promotion
experiment with the topside coke oven extract on C57BL/6 mice done for
comparison with the experiment on SENCAR mice. Similar protocols were used
for the two studies except that the C57BL/6 mice were on study for 52 weeks.
Tumor-initiating activity at the application site was not observed with coke
oven emission sample extract at doses as high as 10 mg/mouse; however,
tumor-initiating activity was also not demonstrated with the positive control
chemical, benzo[a]pyrene, at doses as high as 403.68 ug/mouse. Thus, results
obtained in the experiment on C57BL/6 mice are considered inconclusive as
indicated by the resistance of this mouse strain to tumor-initiating activity
by the positive control agent.
119
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Coal Tar
Carcinogenicity studies on aerosols of coal tar and coal tar fractions in
laboratory animals were reported by Horton (1961), Morton et al. (1963), Tye
and Stemmer (1967), MacEwen and Vernot (1972-1976), Kinkead (1973), McConnell
and Specht (1973), and MacEwen et al. (1976). These studies provide evidence
for a carcinogenic effect of coal tar aerosol test samples as discussed
herein.
Numerous carcinogenicity studies on coal tar samples applied topically to
the skin of laboratory animals have been reported. Studies discussed herein,
which show an ability of coal tar samples to produce local tumors following
skin treatment, include those reported by Bonser and Manch (1932), Hueper and
Payne (1960), Horton (1961), and Wallcave et al. (1971). Horton (1961) and
Wallcave et al. (1971) tested coal tar samples from coking operations.
Inhalation Exposure Studies--
Horton et al. (1963) examined C3H mice (a strain that was reported to have
a low historical incidence of spontaneous pulmonary adenomas) for lung tumors
following inhalation exposure to coal tar aerosol, gaseous formaldehyde, or
gaseous formaldehyde followed by coal tar aerosol. In the first part of the
experiment, groups of 60, 60, and 42 mice were exposed to concentrations of
0.5, 0.10, or 0.20 mg/liter, respectively, of gaseous formaldehyde for three
1-hour periods per week. The control group consisted of 59 untreated mice.
After 35 weeks, none of the animals that were sectioned of those that died
(118 of 221) during the period had developed lung tumors. The surviving
animals were used to conduct further experiments with coal tar and
formaldehyde. The surviving 33 mice from the control group in the first part
of the experiment and the surviving 26 mice from the group that had been
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exposed to 0.10 mg/liter of gaseous formaldehyde in the first part of the
experiment were exposed to 0.30 mg/liter of coal tar aerosol for three 2-hour
periods per week for up to 36 weeks. The surviving 36 mice from the group
that had been exposed to 0.05 mg/liter of formaldehyde in the first part of
the experiment were exposed to 0.15 mg/liter of formaldehyde for three 1-hour
periods each week for up to 35 weeks. Also, the untreated control group* was
observed for 82 weeks.
The test animals were exposed to the test substances until death. The
first death occurred 1 to 11 weeks after exposure and the longest time until
death was 36 weeks. Serial sections of the trachea, large bronchi, and lung
of the exposed animals and sections of the lung of 30 unexposed mice were
examined (Table VI-20).
Five mice inhaling coal tar aerosol and one mouse inhaling formaldehyde
followed by coal tar developed squamous cell tumors in the periphery of the
lung, involving one-third to one-half of the lobe. In two mice from the
former group, several lobes were involved. A sixth mouse in the former group
that died after 20 weeks of exposure had an invasive squamous cell carcinoma,
which was described as "unquestionably a squamous cell carcinoma, whereas,
those occurring in the other five animals probably represented an earlier
stage of development at the time of death." One mouse in each group had
adenoma of the lung. Tumors of the lung were not observed in mice breathing
formaldehyde only or in untreated controls.
There were other changes produced in the tracheobronchial epithelium as the
result of the inhalation of coal tar. The most striking was a necrotizing
tracheobronchitis in the majority of mice; the incidence was not reported. In
*The initial size of the untreated group was not reported. At the
termination of the experiment at 82 weeks, the group consisted of 30 mice.
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TABLE VI-20. TUMORS OF THE LUNG IN MICE INHALING FORMALDEHYDE
AND/OR AEROSOL OF COAL TAR
(adapted from Horton et al. 1963)
Treatment
Untreated
Controls
Coal Tar
Formaldehyde
and Coal Tar
Formaldehyde
Squamous Cell
Tumors
0/30
6/33*
1/26
0/36
(0%)
(18%)
(4%)
(0%)
Adenomas
0/30 (Q%)
1/33 (3%)
1/26 (4%)
0/36 (0%)
Total
0/30
7/33
2/26
0/36
(0%)
(21%)
(8%)
(0%)
"A squamous cell carcinoma was founa in one animal
122
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addition, squamous cell metaplasia extended into the smaller bronchi.
Hyperplasia of the bronchial epithelium occurred frequently, sometimes with
papillary infolding. The epithelium of untreated mice was normal, showing
neither metaplasia nor hyperplasia.
Epithelial changes in mice inhaling formaldehyde involved mostly the
trachea; extension into the major bronchi was infrequent and did not occur at
all in the smaller bronchi. In general, the inhalation of formaldehyde
resulted in an acute tracheobronchitis ranging from slightly to severely
necrotizing, or developing into a chronic type with proliferation of fibrous
tissue. This was sometimes complicated by bronchopneumonia. In summary, mice
inhaling coal tar aerosol developed squamous cell carcinomas of the lung, as
well as hyperplastic and metaplastic epithelial changes.
Tye and Stemmer (1967) separated two different coal tars into phenolic
(P-tar) and nonphenolic (N-tar) fractions and exposed mice by inhalation to
various blends of the coal tar fractions and to one of the original tars. The
same coal tar (T-l) (specific gravity 1.17; 4.5% tar acid, 0.7%
benzo[a]pyrene, and 67% Diels-Adler compounds*) that was used in the
experiments by Horton, Tye, and Stemmer (1963) and a second, somewhat
different tar (T-2) (specific gravity 1.24; 1.4% tar acid, 1.1%
benzo[a]pyrene, and 2% Diels-Adler compounds*), were the two tars from which
the phenolic (P-tar) and nonphenolic (N-tar) fractions were separated.
Fifty male C3H/HeJ mice, 3 to 5 months old, were in each test group. The
tests groups consisted of untreated, Tar-1, N-Tar-1, N-Tar-1 plus P-TAR-1,
N-Tar-1 plus P-Tar-2, and N-Tar-2 plus P-TAR-1. Mice were exposed for 2 hours
*As indicative of anthracene and polycyclic aromatic hydrocarbons with
three linear aromatic rings with a free meso position.
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every 3 weeks. During the first 8 weeks, the exposure was at a concentration
of 0.20 mg/liter, but this was reduced to 0.12 nig/liter because so many mice
died.
Three mice from each group were killed after 4 weeks, and five mice were
killed after 31 weeks. Surviving mice were killed at the end of 55 weeks.
Mortality from exposure was high in all groups of treated mice. At the end
ofthe experiment, there were 31/50 (62%), 11/50 (22%), 11/50 (22%), 10/50
(20%), 21/50 (42%), and 21/50 (42%) mice alive in the control, Tar-1, N-Tar-1,
N-Tar-1 plus P-Tar-1, N-Tar-1 plus P-Tar-2, and N-Tar-2 plus P-Tar-1 groups,
respectively. _Tumor response is recorded in Table VI-21.
The most prominent lesions were intrabronchial adenomas and
adenocarcinomas, occurring anywhere in the bronchial tree. Multiple tumors
were frequently seen. The intrabronchial adenomas were papillary. There also
were alveolar adenomas which were peripheral. Tumors of the lung were
diagnosed as adenocarcinomas only if there was invasion or if metastases were
observed.
Adenomas and adenocarcinomas of the lung were observed in 60% to 100% of
the mice inhaling aerosols of coal tars, whereas tumors were not seen in any
of the control mice. Incidences of squamous metaplasia varied from 10% to 38%
in treated mice and were absent in control mice. "Alveolar epithelization"
was also observed, but less often than squamous metaplasia. Areas of squamous
and alveolar metaplasia were not considered as tumors, even when they occupied
relatively large spaces.
MacEwen and Vernot (1972-1974), Kinkead (1973), and McConnell and Specht
(1973) reported on a study in which mice, rats, hamsters, and rabbits were
exposed to a coal tar aerosol from which the light oil and solid fraction was
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TABLE VI-21. INCIDENCE OF LUNG TUMORS IN MICE INHALING AEROSOLS OF COAL TARS*
(adapted from Tye and Stemmer 1967)
Treatment
Untreated
Controls
Tar-1
N-Tar-1
N-Tar-lt
P-Tar-1
N-Tar-lt
P-Tar-2
N-Tar-2t
P-Tar-1
Metaplasia
0/32
5/13
2/20
5/19
7/25
4/23
(0%)
(38%)
(10*)
(26%)
(28%)
(17%)
Adenomast
0/32
12/13
16/20
14/19
14/25
14/23
(0%)
(92%)
(80%)
(74%)
(56%)
(61%)
Adenocarcinomas
0/32
3/13
0/20
1/19
1/25
0/23
(0%)
(23%)
(0%)
(5%)
(4%)
(0%)
Adenomas and
Carcinomas
0/32
13/13
16/20
15/19
15/25
14/23
(0%)
(100%)
(80%)
(79%)
(60%)
(61%)
*Mice surviving for 46 weeks or longer.
tlncludes intrabronchial and alveolar adenomas.
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removed. Gross skin pathology for the mice was reported; any other tumor
response in the mice and in the other animals was not reported.*
Groups of 64 female yearling and 64 weanling (32 of each sex)
Sprague-Dawley rats, 50 male JAX-CAF1 mice, and 50 male ICR-CF1 mice were
exposed continuously for 90 days (except for 15 minutes a day to allow for
animal maintenance) to concentrations of 0.2, 2.0, and 10.0 mg/m^ of coal
tar aerosol. Ninety-two female yearling Sprague-Dawley rats, 82 weanling
Sprague-Dawley rats (73 female and 9 male), 75 male JAX-CAF1 mice, 75 male
ICR-CF1 mice, 100 male golden Syrian hamsters, and 24 New Zealand white
rabbits were exposed continuously, as above, for the same 90-day period to a
concentration of 20 mg/m3. The control animals consisted of 41 female and
41 male Sprague-Dawley weanling rats, 82 female Sprague-Dawley yearling rats,
75 male JAX-CAF1 mice, 75 male ICR-CF1 mice, 24 female New Zealand white
rabbits, and 100 male golden Syrian hamsters (MacEwen and Vernot 1972). Many
of the mice contracted a streptococcus infection and died before 93 days
postexposure. Skin tumor response for the mice is found in Table VI-22.
Tumor responses of 28% (10 of 36), 38% (3 of 8), and 8% (2 of 25) were
seen in the three highest dose groups of the ICR-CF1 mice; no tumors (0 of 62)
were found in the controls. A tumor response of 37% (10 of 27) was found in
the highest dose group JAX-CAF1 mice; no tumors (0 of 74) were found in the
JAX-CAF1 controls. McConnell and Specht (1973) examined some of the skin
tumors histologically and concluded that a whole spectrum of epithelial
tumors, from squamous cell papilloma to keratoacanthoma to "frankly
aggressive" appearing squamous cell carcinoma are stimulated by the coal tar
aerosol, although the majority of these tumors fall in the squamous cell
*Per contractual agreement, Sasmore performed internal and skin
histopathology for the study and reported his results (Sasmore 1976), but
because information in the Sasmore report is incomplete, no conclusions can be
made about the report.
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TABLE VI-22. TUMOR RESPONSE IN MALE ICR-CF1 AND JAX-CAF1 MICE
FOLLOWING EXPOSURE TO COAL TAR AEROSOL
(adapted from McConnell and Specht 1973)
Dose (mg/m3) ICR-CF1* JAX-CAF1*
20.0 10/36 (28%)t 10/27 (37*)t
10.0 3/8 (38%)S 0/12 (OX)S
2.0 2/25 (8S)§ 0/47 (OS)§
0.2 0/2 (0*)S 0/47 (0%)S
0.0 0/62 (0%)t 0/74 (0%)t
*The numerator is the number of animals with tumors at 415 days
postexposure. The denominator is the number of animals that were alive at 93
days postexposure.
tThis dose group began with 75 animals.
§This dose group began with 50 animals.
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category. McConnell and Specht also found a time-to-tumor dose-response for
the coal tar aerosol. This dose-response is shown in Table VI-23. As stated
above, tumor response was not reported for the rats, hamsters, or rabbits.
MacEwen and Vernot (1975 and 1976) and MacEwen et al. (1976) reported on
two studies of the tumor response of mice, rats, rabbits, and monkeys
following exposure to coal tar aerosol. In the first study, 80 female
Sprague-Dawley yearling rats, 80 Sprague-Dawley weanling rats (40 males and
40females), 75 JAX-CAF1 male mice, 75 ICR-CF1 male mice, and 100 male Syrian
golden hamsters were exposed continuously for 90 days (except for 15 minutes a
day to allow for animal maintenance) to concentrations of 0.2, 2.0, and 10.0
mg/m3 of coal tar aerosol. An equal number of each species were used for
controls. The coal tar used to generate the aerosol in this study was:
a composite mixture collected from multiple coking ovens around
the greater Pittsburgh area. The coking ovens were of several
different types and used different coal sources for their starting
materials. The coke oven effluents were collected in air collec-
tion devices using a chilled water spray to condense the higher
boiling distillate fractions. After settling and separation of the
liquid phase, the various coal tar samples were blended together
with a 20% by volume amount of the BTA (benzene, toluene, xylene)
fraction of the coke oven distillate.
An aerosol particle size determination in the exposure chambers was performed,
and it was found that a minimum of 97% of all droplets were in a respirable
range of 5 microns or less in diameter. Only skin tumor response for the mice
was reported (Table VI-24). Tumor response was not reported for the hamsters
or rats.
In the second study, 75 female and 100 male ICR-CF1 mice (described as
tumor susceptible), 50 female JAX-CAF1 mice (described as a tumor-resistant
hybrid strain), 40 male and 40 female CFN strain Sprague-Dawley weanling rats,
18 New Zealand albino rabbits, and 5 male and 9 female Macaca mulatta monkeys
128
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TABLE VI-23. LATENT PERIOD OF FIRST TUMOR INDUCTION IN CTV-I EXPOSED
ICR-CF1 MICE
(McConnell and Specht 1973)
Dose (mg/m3)
20
10
2
Time of Tumor Appearance (Days)
< 93
128
142
TABLE VI-24. SKIN TUMOR RESPONSE IN ICR-CF1 AND JAX-CAF1 MICE FOLLOWING
EXPOSURE TO COAL TAR AEROSOL
(MacEwen and Vernot 1976)
Cumulative Number of Tumors*
Dose
(mg/m3)
10
2
0.2
Week of
Observationt
100
103
101
Exposed
44/75 (59%)
14/75 (19%)
1/75 (1%)
ICR-CF1
Control
3/75 (4%)
0/75 (0%)
0/75 (0%)
Exposed
18/75 (24%)
3/75 (4%)
1/75 (1%)
JAX-CAF1
Control
1/75 (1%)
0/75 (0%)
1/75 (1%)
numerator is the number of animals with tumors; the denominator is
the number of animals exposed.
tlncludes the 90-day exposure period.
129
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were exposed to 10 mg/m^ of coal tar aerosol for 6 hours each day, 5 days
per week, for 18 months. The coal tar used to generate the aerosols in this
study was the same as that of the first study. Aerosol particle size was
determined monthly in the exposure chambers. A minimum of 99% of the total
droplets in both chambers were 5 microns or less in diameter and were thus
within a respirable size range for rodents.
Exposure to the coal tar at 10 mg/m^ significantly reduced the body
weight of rabbits and rats compared with the controls, whereas monkeys showed
no significant change in body weight. Sixteen of 18 rabbits and 6 control
mice died during the test period. These deaths were attributed to a chronic
respiratory infection which caused debilitation and dehydration. At the
conclusion of the exposure period, the test monkeys and the surviving test
rabbits along with the unexposed controls were delivered to the National
Institute for Occupational Safety and Health (NIOSH) Laboratories in
Cincinnati, Ohio. Since the number of surviving rabbits (2 of 18) was too few
for statistical comparison, and those animals were sacrificed (Gibb 1978a), no
tumor response was found in the sacrificed rabbits (Gibb 1978b). The monkeys
were kept for observation at the NIOSH Laboratories until 1979 when they were
moved to Gulf South Research in New Iberia, Louisiana, where they are
currently being maintained. One of the dosed monkeys died in 1981; results of
the autopsy are not yet available (Gibb 1981).
Alveolargenic [sic] carcinomas were produced in 26 of 61 (43%) ICR-CF1
mice and in 27 of 50 (54%) JAX-CAF1 mice. The number of tumors in the ICR-CF1
and the JAX-CAF1 control mice were 3 of 68 (4%) and 8 of 48 (17%),
respectively. The exposed and control groups did not differ in the incidence
of other types of tumors including squamous cell carcinomas, lymphosarcomas,
130
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subcutaneous sarcomas, alveolargenic adenomas, bronchiogenic carcinomas,
reticulum cell sarcomas, hemangiosarcomas, and hemopoietic tumors.
Skin tumors were produced in 5 of 75 (7%) of the ICR-CF1 mice and 2 of 50
(4%) of the JAX-CAF1 mice as compared to 3 of 75 (3%) and 1 of 50 (2%) in the
ICR-CF1 and JAX-CAF1 controls, respectively. The criterion for counting a
lesion as a skin tumor was a growth greater than 1 mm in diameter and in
height. Each tumor was ultimately confirmed by histologic examination.
MacEwen et al. compared the lack of skin tumor response in the second study to
the tumor response of the 10 mg/m^ dose group of the first study. As stated
previously, the first study found a skin tumor incidence of 14 of 75 (59%) in
the treated ICR-CF1 controls and 18 of 75 (24%) in the treated JAX-CAF1 mice
as opposed to only 3 of 75 (4%) in the ICR-CF1 controls and 1 of 75 (1.3%) in
the JAX-CAF1 controls, respectively. A calculation of total exposure time
(MacEwen et al. 1976) revealed that the same amount of coal tar aerosol
reached the skin of mice in the second study as in the first study. MacEwen
et al. suggested that the 18-month intermittent exposure of the animals in
their study allowed the animals enough time each day to permit normal cleaning
of the fur.
The incidence of coal tar tumorigenesis in rats is reported in Table
VI-25. The incidence of squamous cell carcinomas in the lungs was 100%
(38/38) in exposed males and 82% (31/38) in exposed females as opposed to 0%
(0/36) in male controls and 0% (0/37) in female controls.
A dose-related tumor response was observed for both the ICR-CF1 and the
JAX-CF1 mice.
131
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TABLE VI-25. COAL TAR TUMORIGENESIS IN RATS
(MacEwen et al. 1976)
Controls Exposed
Males Females Males Females
Number Examined Histologically*
Number of Rats with Tumors:
Squamous Cell Carcinoma, Lung
Squamous Cell Carcinoma
Intra-abdominal Carcinoma
Mammary Fibroadenoma
Mammary Adenocarcinoma
Other Tumors
Overall Tumor Incidence (%)
30
0
0
0
0
0
0
0
37
0
1
1
1
1
1
13
38
38
0
0
0
0
8
100
38
31
0
0
3
0
2
82
*The original number of rats per group was 40. However, because of
autolysis and/or cannibalization, a few animals were unsuited for
histopathological examinations.
Topical Application Studies--
Bonser and Manch (1932) studied the tumor response from application to
mouse skin of three samples of Scottish blast-furnace tar, one sample of
English crude tar, and an ether extract of the latter. The three samples of
Scottish tar (I, II, III) were made from coke oven charges which contained in
addition to the coal, 15 to 17%, 25%, and 10% coke, respectively; the English
crude tar was made from a charge containing 75% coal and 25% coke. Sixty mice
were used for testing each sample of tar. There were no negative and positive
control groups. The hair was clipped away from a small area of skin in the
region between the shoulder blades. The tar was applied biweekly for the
first 14 weeks, and thereafter once weekly because of marked ulceration of the
skin of many mice. Tar samples were used without indication of further
preparation in solvent. The study was continued for 56 weeks, by which time
all the mice had died. Fifty-seven tumors were grossly identified. Thirty-
one of the total 57 tumors that had developed were confirmed histologically.
132
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Tumor findings are described in Table VI-26. In mice treated with the
three Scottish samples, the first tumors appeared at the 18th week. The
Scottish I, II, and III tar samples produced a tumor incidence of 7/60 (12%),
10/60 (17%), and 8/60 (13%), respectively. The tumors were malignant in three
mice. The first tumor appeared at the 21st week when an English crude tar was
used. Eight mice (13%) treated with the English crude tar developed tumors as
did 24 mice (40%) treated with an ether extract of the English crude tar.
Nine tumors in mice given the ether extract were malignant.
The tumors were papillomas or squamous cell carcinomas of the skin. The
carcinomas invaded the muscle. One malignant tumor, seen after 47 weeks of
application of ether extract of English tar, consisted of a mass of
"mononuclear round cells" invading the adjacent muscle and fat and
metastasizing to the lymph nodes.
TABLE VI-26. INCIDENCE OF SKIN TUMORS IN MICE TREATED WITH BLAST FURNACE TARS
(adapted from Bonser and Manch 1932)
Tar Sample
Scottish I
Scottish II
Scottish III
English Crude
Number of Animals
with Tumors/
Number of Animal s
7/60
10/60
8/60
8/60
(12%)
(17%)
(13%)
(13%)
Appearance of
First Tumor Malignant
(weeks) Tumors
16
16
16
21
0/60
2/60
1/60
0/60
(0%)
(3%)
(2%)
(0%)
Ether Extract
of English Crude
24/60 (40%)
12
9/60 (15%)
133
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Hueper and Payne (1960) found that skin tumors were produced in mice
following the application of coal tar. Coal tar, four petroleum road asphalts
(Venezuelan, Mississippian, Oklahoman, and Californian), one petroleum roofing
tar, and paraffin oil were applied to the napes of the necks of groups of 50
black C57 mice (25 of each sex) for 2 years. An untreated control group
consisted of 200 mice. A positive control group was not used in this study.
So that the materials could be applied as droplets, the coal tar and roofing
asphalt were heated to make them liquid, and the road asphalts were diluted
with a sufficient amount of acetone. The paraffin oil was painted on the
skin. Post-mortem examinations were performed on all mice, and histological
examinations were made of all tissues which exhibited gross abnormalities.
The results are found in Table YI-27.
Carcinomas of the skin were found in 22 of 50 (44%) and papillomas in four
of 50 (8%) mice receiving dermal applications of coal tar, whereas control
mice did not develop tumors of the skin.
Hueper and Payne also administered some of the substances via inhalation
and intramuscular injection. Daily volatilization of 10 to 30 g of coal tar
did not produce lung tumors in female Bethesda black rats or strain 13 guinea
pigs inhaling the fumes 5 hours daily, 4 days per week, for periods up to 2
years. However, coal tar distillate produced muscle sarcomas in 50 of 100
mice given 6 biweekly intramuscular injections and observed for a duration of
2 years.
Horton (1961), in several experiments, tested a number of crude coal tars,
coal tar distillates, and fractions of coal tar for skin tumor response in C3M
mice. In the first part of the study, five coal tars (four from the coking of
bituminous coal and one from the coking of lignite coal), a mixture of one
134
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TABLE VI-27. SKIN TUMORS IN MICE GIVEN DERMAL APPLICATIONS OF COAL TAR,
PETROLEUM ROOFING TAR, PARRAFIN OIL, OR PETROLEUM ROAD ASPHALTS
(adapted from Heuper and Payne 1960)
Treatment
Control
Coal Tar
Petroleum Roofing Tar
Paraffin Oil
Petroleum Road Asphalt
Venezuelan
Mississippian
Oklahoman
Californian
Skin
Carcinomas
0/200
22/50
1/50
1/50
0/50
1/50
0/50
1/50
(0%)
(44%)
(2%)
(2%)
(0%)
(2%)
(0%)
(2%)
Skin
Papillomas
0/200
4/50
0/50
1/50
0/50
1/50
1/50
0/50
(0%)
(8%)
(0%)
(2%)
(0%)
(2%)
(2%)
(0%)
Total
0/200
23/50
1/50
2/50
0/50
2/50
1/50
1/50
(0%)
(46%)
(2%)
(4%)
(0%)
(4%)
(2%)
(2X)
135
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of the bituminous coal tars in 50% benzene, and a benzo[a]pyrene mixture were
tested. The authors did not report using a control group. No data were
provided on the number of mice tested nor on the length of time the animals
were treated; however, the time-to-tumor for each group was reported. The
incidence of tumors was reported to be greater than 75% (only a percentage was
reported) for each test group. Horton developed a numerical index designed to
grade the various tars and tar fractions for relative carcinogenic potency.
This index was referred to as the potency for a minimum concentration of
material (PMC). A high PMC value was meant to indicate a greater carcinogenic
potency. For tars D-l and D-613, for which multiple doses were applied, a
dose-response was evident. The mean time-to-tumor (in weeks), the schedule of
application, and the PMC values for each of the tars, the tar solution, and
the benzo[a]pyrene solution are reported in Table YI-28.
Two tars from the previous group (D-l and -D-8) were chosen to test the
effect of skin washing with a detergent in water 5 to 60 minutes after tar
application. Tars D-l and D-8 had the highest (0.8) and lowest (0.1)
benzene-insoluble content, respectively. Washing delayed tumor development,
but the final tumor incidence was not significantly changed. The delay was
greater in the animals washed 5 minutes after dermal application.
Horton also determined the relationship between the amount of
benzo[a]pyrene in distillates of coal tar and the carcinogenic potency of
those distillates. Tar D-l, a distillate oil of D-l (the first 9 to 13.5% of
the distillation), a proportionate reblend of nine distillate fractions of D-l
and two distillate fractions (a carbolic oil and a light creosote oil) of a
coal tar (D-9) not previously used in the experiments, were tested for BaP
content and carcinogenic potency (PMC) to the skin of mice. With the
exception of Tar D-l, all test materials were applied to mice (strain
136
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TABLE VI-28. MEAN TIME-TO-TUMOR AND PMC VALUES FOR FOUR BITUMINOUS TARS,
ONE LIGNITE TAR, AND ONE SOLUTION OF BENZO[A]PYRENE
(adapted from Morton 1961)
Schedule of
Application Mean Time-to- PMC*
Treatment (Doses/week - mg/Dose) Tumor (weeks)
D-l
D-4
D-5
D-5A
D-8
D-12
D-613
- bituminous tar
- bituminous tar
- bituminous tar
- 50% dilution
by weight of
D-5 tar
- bituminous tar
- lignite tar
- benzo[a]pyrene
in 85% beta-
methyl naphthal ene
and 15% benzene
solution
2-10
2-50
3-100
2-10
2-10
2-10
3-50
3-50
2-15
2-50
15. 6t
12. 6t
7.0t
24.8
23.6
25.1
21.9
17.1
33. Ot
30. 6t
0.27t
0.37t
0.63t
0.13
0.14
0.13
0.11
0.16
o.oat
O.lOt
*PMC: Potency for minimum dose of test sample, i.e., the PMC increases as
carcinogenic potency increases.
tThe multiple doses for Tars D-l and D-613 demonstrated a mean time-to-
tumor and a PMC dose-response.
137
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unspecified) in 10 mg doses. Tar D-l was applied in 20 mg doses. The number
of applications was described as "repeated," but neither the frequency nor the
duration was specified. The PMC values and benzoEalpyrene content of the test
substances are reported in Table VI-29.
Comparison of the benzo[a]pyrene content with the carcinogenic potencies
of various fractions showed that no tumors were produced by those fractions in
which no benzo[a]pyrene could be detected, while the carcinogenic potency of
the test materials that contained benzo[a]pyrene was correlated with their
content by weight of this carcinogen. Despite this observation, the authors
did caution that these results do not imply that benzo[a]pyrene is the only
carcinogen in these substances.
TABLE VI-29. PMC VALUES AND BENZO[A]PYRENE CONTENT FOR TWO COAL TARS, SEVERAL
DISTILLATES OF THOSE COAL TARS, AND A PROPORTIONATE REBLEND OF THE DISTILLATES
FROM ONE OF THE TARS
(adapted from Norton 1961)
Test Material
Tar D-l
Distillate Oil of
Doses (mg)
20
10
Content of
Benzo[a]pyrene (%)
0.74
0.01
Relative Carcinogenic
Potency (PMC)
0.27
0.01
Tar D-l
Proportionate Reblend 10 0.08 0.11
the Nine Cuts of
Tar D-l
Carbolic Oil of Tar
D-9 10 0.00 0.00
Light Creosote Oil 10 0.00 0.00
of Tar D-9
138
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Wall cave et al. (1971) prepared benzene extracts of coal tar pitches
obtained from coke ovens and tested them for carcinogenic activity on mouse
skin. Equal numbers of male and female Swiss albino mice received twice
weekly applications of 1.7 mg of coal tar pitch in 25 ul of benzene. Exposed
animals survived for an average of 31 weeks. Among 58 treated mice, 53
developed skin tumors, of which 31 were carcinomas. Although tumors at other
sites were present, the incidence in the control and experimental groups were
similar. No carcinomas and only one papilloma on the skin were found in 26
control mice painted with benzene alone. Wallcave et al. (1971) identified
several polycyclic hydrocarbons, including benzo[a]pyrene (0.84 and 1.25% of
undiluted coal tar pitch in 2 samples), in the pitch samples and concluded
that they were responsible for the tumorigenie effects observed.
139
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CARCINOGENICITY OF COKE OVEN EMISSION COMPONENTS
Polycyclic Organic Matter (POM)
Numerous polycyclic aromatic compounds are distinctive in their ability to
produce tumors in skin and most epithelial tissues of practically all species
tested. Malignancies are often induced by acute exposures to microgram
quantities of POM (for a review, see U.S. EPA 1979). Latency periods can be
short (4 to 8 weeks) and the tumors produced may resemble human carcinomas.
Carcinogenesis studies involving POM have historically involved primarily
effects on the skin or lungs. In addition, subcutaneous or intramuscular
injections are frequently employed to produce sarcomas at the injection site.
Ingestion has not been a preferred route of administration for the bioassay of
POM. A listing of POM found in coke oven emissions is presented in Table
VI-30 along with an indication of carcinogenic activity.
Other Carcinogens Identified in Coke Oven Emissions
The contribution of compounds other than POM to the carcinogenic activity
of coal combustion products has received little attention. Other constituents
of coke oven emissions that have been found to be carcinogenic include
arsenic, lead, beryllium, chromium, nickel, 2-naphthylamine, and benzene (U.S.
EPA 1977a; 1978b, c; 1980n; IARC 1973b; 1974; 1976; 1979).
Cocarcinogens
Numerous compounds, which by themselves display no carcinogenic activity,
are known to enhance the tumorigenic activity of B[a]P when applied together
to the skin of mice (Hoffman et al. 1978, Van Duuren and Goldschmidt 1976).
These so-called cocarcinogens include certain PAH-containing fractions of
tobacco tar, and several structurally diverse compounds (catechol, pyrogallol,
140
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TABLE VI-30. POLYCYCLIC ORGANIC MATTER (POM) IDENTIFIED IN
COKE OVEN EMISSIONS*
Compound Animal Carcinogen!cityt
IARC CAG
Anthracene - +
Benz[a]anthracene +
Dibenz[a,c]anthracene +
Methylphenanthrene
Phenanthrene
Benzo[c]phenanthrene +
Benzo[a]fluorene
Benzo[b]fluorene
Dihydrobenzo[a]fluorene ?
Dihydrobenzo[b]fluorene ?
Dihydrobenzo[c]fluorene § ?
Fluoranthene
Benzo[c]fluorene
Benzo[b]fluoranthene + +
BenzoCjJfluoranthene + +
Benzo[k]fluoranthene
Benzo[ghi]fluoranthene
Pyrene
Methylpyrene
Benzo[ajpyrene + +
Benzo[e]pyrene +
Dibenzopyrenes + +
Chrysene § ±_ +
Triphenylene §
Perylene
Benzo[ghi]perylene §
Anthanthrene § +
Coronene
Acn'dine
Benzoquinol ine
Octahydrophenanthrene ?
Octahydroanthracene ?
Dihydrofluorene ?
Benzindene ?
Fluorene
Dihydrophenanthrene ?
Dihydroanthracene
Methylfluorenes ?
Fluorene Carbonitrile ?
Methyl anthracene
Ethylphenanthrene ?
Ethyl anthracene
(continued on the following page)
141
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TABLE VI-30. (continued)
Compound Animal Carcinogenicityt
IARC CAG
Octahydrofluoranthene § ?
Octahydropyrene § ?
Indeno[l,2,3-cd]pyrene + +
Dibenz[a]anthracene +
Benz[c]acridine + +
Dibenz[a,h]acridine + +
Dibenz[a,j]acridine + +
Dihydrofluoranthene ?
Dihydropyrene ?
Methylfluoranthene +
Dihydrobenz[a]anthracene § T
Dihydrochrysene § ?
Dihydrotriphenylene § ?
Dihydromethylbenz[a]anthracene § ?
Dihydromethylchrysene § ?
Dihydromethyltriphenylene § ?
Methylbenz[a]anthracene +_
Methyltriphenylene +
Methyl chrysene +_
Dihydromethylbenzo[k and b]-
fluoranthenes§ ?
Dihydromethylbenzo[a and e]pyrenes § ?
Dimethylbenz[a]anthracene § + - +
Dimethyltriphenylene §
Dimethylchrysene § +
Methylbenzo[k]fluoranthene § ?
Methylbenzo[b]fluoranthene § ?
Methylbenzo[a]pyrene +
Dimethylbenzo[k and b]-
fluoranthenes ?
Dimethylbenzo[a]pyrene +
o-Phenylenepyrene ?
Methyldibenzanthracene +
Methylbenzo[ghi]perylene ?
*The POM's were identified in coke oven emissions by Lao et al. 1975 or
Bjorseth et al. 1978. The data on carcinogenicity is taken from CAG (1980b)
and IARC (U.S. EPA 1979).
tSymbols: + complete carcinogen or tumor initiator
- negative
? activity not known
+_ may be positive or negative depending on the isomer tested
SConfirmation of chemical structure questionable in Lao et al. (1975).
142
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anthralin, decane, undecane, tetradecane). Since many of these compounds may
occur in coke oven emissions, the possibility arises that they may contribute
to carcinogenic risk. However, the mechanism of cocarcinogenesis is not
understood, and its relevance to tumor formation in tissues other than mouse
skin is not known. Thus, we can only conclude that the presence of
cocarcinogens in complex mixtures such as coke oven effluents may pose an
additional risk for humans beyond that attributable to recognized carcinogens
such as benzo[a]pyrene.
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VII. UNIT RISK ESTIMATE
The shortest possible period of time from the initiation of an event due to
an exposure to a carcinogen to death or diagnosis of cancer caused by the event
is defined here as the "minimum initiation time." The "minimum initiation time"
is an important factor that should be taken into consideration whenever an
attempt is made to determine the relationship between the level of exposure and
subsequent cancer incidence or mortality. This is particularly true when human
epidemiological or animal data based upon an exposure and/or follow-up of less
than a full lifespan is utilized to establish the dose-response relationship.
Mazumdar et al. (1975) generated an extensive data base concerning the
exposure to coke oven emissions and the respiratory cancer death rates of black
steel workers. A cancer mortality model is developed in this report and is
fitted to the Mazumdar et al. (1975) data to estimate the "minimum initiation
time" and respiratory cancer potency associated with coke oven emissions. The
derived "minimum initiation time" and potency estimates are then used to
estimate the "unit risk" of coke oven emissions, where the unit risk is the
lifetime probability of respiratory cancer death due to a continuous lifetime
exposure of 1 ugm/m^ of coal tar pitch volatiles.
MATHEMATICAL MODEL RELATING EXPOSURE TO AN ENVIRONMENTAL HAZARD TO PROBABILITY
OF DEATH DUE TO A SPECIFIED CAUSE
The estimation of the probability of occurrence of a disease in the presence
of competing causes of death is a problem that has received considerable
attention. Chiang (1968, pp. 242-268) has given a general solution to the
problem using standard methods in competing risk analysis. Gail (1975), using
these methods, gives a simple and detailed derivation of the probability of a
144
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disease being caused by an environmental hazard by time t, that may be expressed
as:
t
P(t,x) = / h2[X(v),v] S(v)dv
o
where
v
- / {hi(s) + h2[X(s),s]}ds
S(v) = e o
is the probability of survival until age v,
h]_(s) = the total age-specific death rate at age s in the absence of the
environmental hazard of concern, and
h2[X(s),s] = the age-specific death rate at age s due to X(s), the prior
exposure pattern of the environmental hazard.
Knowledge of the exact form for h2[X(s),s] would depend upon a detailed
understanding of the mechanism by which the environmental hazard causes the
disease. For the case of cancer, such an understanding does not presently
exist. As a result, it is necessary to postulate a form for h2CX(s),s] that
is based upon as few and as simple a set of assumptions as is possible that
still gives predictions which are consistent with observed results.
Taking this approach we define the following terms:
92Cx(v),v] = the instantaneous probability of the initiation of an event at
time v caused by an exposure to an environmental agent at level
x(v), that ultimately will lead to death in the absence of
competing mortality, and
w(t-v) = the probability distribution of the time from the initiation of the
event until death in the absence of competing mortality.
Using these definitions, it follows that the age-specific or instantaneous
145
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death rate due to the environmental hazard at time t is
t
h2CX(t),t] = / g2[x(v),v]w(t-v)dv .
o
Assuming events are initiated linearly proportional to exposure at that
time, the instantaneous initiation probability may be written as
92[x(v),v] = Ax(v)
If we assume that a fixed initiation time "I" must pass before death can
occur from an initiated event, but beyond that time the probability of death
occurring is equal for all times for a duration of length R after which it again
becomes zero, then it follows that:
o v <_ t-I-R
w(t-v) = w*(v) = l/R t-I-R < v <_ t-I
o t-I < v
Thus, given the exposure pattern x(v), o <_ v £ t, the instantaneous death
rate at time t due to that exposure is
t
h2[X(t),t] = / Ax(v)w*(v)dv .
o
The utility of this model will depend upon its ability to predict observed
results within normal statistical variability. Its utility in predicting the
occurrence of respiratory cancer in a population exposed to coke oven emissions
is explored in the next section.
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MODEL APPLIED TO EFFECTS OF COKE OVEN EMISSIONS ON RESPIRATORY CANCER RATES OF
NONWHITE MALE STEELWORKERS
In a series of papers, Lloyd et al. (1970), Lloyd (1971), Redmond et al.
(1972), and Redmond et al. (1976) presented their findings concerning
respiratory cancer death in a cohort of nonwhite steel workers followed over a
15-year period. Mazumdar et al. (1975) calculated the total mg/m3 months of
exposure to coal tar pitch volatiles for each worker. This was done by taking
the sum over all job classifications of the products of the estimated exposure
in a specified job classification by the number of months worked in that
classification.
Land (1976) grouped these data into age intervals at the start of the
observation period and obtained average ages and exposures for the grouped data.
To obtain more stable estimates of the respiratory cancer rates, the data were
grouped into larger age intervals and the average exposures and ages
recalculated for use in the subsequent analysis. The results of this
recalculation and the basic observed epidemiological data are presented in
Table VII-1, along with the definitions of the symbols used to represent the
types of epidemiological data.
Estimation of Exposure Pattern
The actual timing of the exposure is unknown to us; we are given only the
totals. However, as a first approximation we assume that exposure was uniform
over time and occurred over the maximum possible time frame. This time frame is
considered to be from age 18, the earliest possible age at first employment, to
the age at the end of the observation period or retirement at age 65, if that
came first.
147
-------
TABLE VII-1. SUMMARIZATION OF GIVEN DATA ON NONWHITE STEELWORKERS
(adapted from Land 1976)
Nonwhite Male Steelworkers Exposed to Coke Oven Emissions
Control s
Nonwhite Male Steelworkers
Not Exposed to Coke Oven
Emissions
s
Average
Age in
Interval
24.24
34.51
44.25
53.54
63.04
X
Average Cumulated
Exposure in mg3
Months 4 12
11.82
20.66
30.44
43.66
40.62
N
Number of
Individuals
in Cohort
912
795
561
344
70
W
Man-Years
of
Observation
12,695
11,251
7,615
4,342
727
0
Observed Number
of Respiratory
Cancer Deaths
3
10
17
17
5
W*
Man-Years
of
Observation
28,047
18,505
13,927
8,770
2,062
0*
Observed Number
of Respiratory
Cancer Deaths
1
3
11
12
1
148
-------
Under these assumptions it follows that the exposure at age v may be
expressed as
X/(t* - 18) 18 < v < t*
x(v) =
o elsewhere
where X is mg/m3 - years and t* is the smaller of 65 and the age at the end of
the observation period.
Derivation of Form of Age-Specific Respiratory Cancer Death Rates Due to
Coke Oven Emissions
Using the previous definition for x(v) and the additional simplifying
assumption that R > t-I, it follows that
o t <_ 18+1
t
h2 [X(t),t] = / AX(V)W*(V) = AX(t-I-18) 18+1 < t £ t* + I
o R (tx -
AX/R t*+I < t
In other words, this says simply that: 1) the age-specific cancer rate increase
due to coke oven emission is not affected until a waiting period of length I
after first exposure at age 18, 2) after this time the age-specific rate
increases in a linear manner for a length of time equal to the assumed maximum
exposure time reaching a maximum at a time that is length I after the last
exposure, and 3) from this point on the rate remains constant at this maximum
level.
The unknowns in this derived relationship are A, R, and I; however, under
the assumption R > t-I, only the ratio, <5 = A/R, and I can be estimated.
149
-------
Derivation of the Expression for the Expected Number of Respiratory
Cancer Deaths in Each Cohort
Consider a cohort of our coke oven exposed population whose average age at
the start of the observation period is s. Under our risk model and the
assumptions:
(1) each individual in the cohort is identical in regards to age and
exposure pattern, and
(2) the background respiratory cancer rate h2(v) is independent of the
coke oven-caused respiratory cancer rate.
The expected number of total respiratory cancer deaths in the m years of the
observation period is
s+m
E(x,m) = / {h2(v) + h2Cx(v),v]} N(v)dv
s
where N(v) is the number of individuals under observation in the cohort at time
or "age" v.
The values for N(v) are not known. All that is given is the total man-years
of observation W and N(s), the number of individuals in the cohort at the time
of the start of the observation period. However, under the approximate
assumption that the fraction r of individuals lost from the cohort for all
reasons is constant over time, it follows directly that
s+m s+m /. i
W=/ N(t) = N(s) / irtt"s) dt = N(s) [l-erm]
150
-------
Since for each cohort, W, N(s), and m are given, the unknown r can be
estimated from the non-linear equation
W . (l-e-n/r = 0
TUT)
Solving this equation for each cohort gives the values shown below:
Cohort Age r
<_ 29 0.010091
30-39 0.007834
40-49 0.013549
50-59 0.023716
> 60 0.052435
Thus for each cohort
-r(t-s)
N(t) = N(s)e
In addition, we assume that for a given cohort the background age-specific
respiratory cancer death rate is constant throughout the entire observation
period and equal to the observed control rate. In terms of our notation, this
assumption is equivalent to assuming
h2(v) = 0*/W* s <_ v <_ s + m
Substituting these approximations for h2(v) and N(v) into the expected value
equation, along with h2Cx(v), v] which was previously derived, gives the
151
-------
result:
E(x,m) = WO*/W* + 66(1)
where
0 s < 1+3
XM(s) {jr(18+I-sL irm[r(s+m-I-18)+l]} 1+3 < s <_ 1+18
It*-18)r2
G(I) = XN(s) { W Cl+r(s-I-18)]-merm} 1+18 < s £ 1+50
(t*-18)r TITT)
XN(s) [(s-I-18)r+l-(l+47r)er(65+I"s)j
(t*-18)r2 1+50 < s £ 1+65
+ XN(s) [
r
XW 1+65 < s
The expected number of deaths so defined can be used in conjunction with the
observed number of deaths in order to estimate the unknown parameters 6, I, in
the manner indicated in the next section.
ESTIMATION OF THE UNKNOWN PARAMETERS 1,6
To estimate the unknown parameters 1,6 , the assumption that to a close
approximation the number of respiratory cancer deaths in an age-cohort is a
Poisson random variable with mean E(x,m) is made. Using this assumption the
maximum-likelihood solution to the unknown parameters is found in the following
manner.
152
-------
The likelihood of the observed values may be written as
all cohorts
and
InL a £ -[0*W/W* + 66(1)] + Oln [0*W/W*+ 66(1)]
all cohorts
For an assumed value of I the maximum likelihood estimator of is obtained
by solving the equation
dlnl = I - 6(1) + OW*6(I) = 0
~ST WO*+W* 66(1)
all cohorts
To find the joint maximum likelihood estimator for 6,1, the maximum
likelihood estimates for 5 were found for a series of I values 0.1 units apart.
The fixed value of I and its corresponding maximum likelihood estimate 6(1) were
then substituted into the likelihood equation to obtain the numerical estimates
L(I). These estimates L(I) were next plotted against I. The values of this
plot are shown in Figure VII-1. The point I0 where L(I0) is a maximum along
with its corresponding value 6(I0) are the joint maximum likelihood estimates
for I and 6 .
Proceeding in this manner, it was found that I0 = 11.4 and 6(I0) =
9.7646 x 10~5. These values are then substituted into the equation E(x,m) to
obtain numerical estimates of the expected number of cases in each of the
cohorts under the assumed model .
153
-------
r
Ct
1C
03 >
ilUA
rcj
Besr:
'$ /«(
I 4
J
2-0
18
-A
Mf
\ .
•A-
4S"
- V
/-o
•8
\
-Z
.0
10
I?.
/»
154
-------
EVALUATION OF THE GOODNESS OF FIT OF THE MODEL
Of obvious interest is how well the developed model fits the observed data.
We calculate the expected number of respiratory cancer deaths in each cohort
from the relationship
E(x,m) = 0*W/W* + 9.7646 x 6(11.4) x 10~5 .
The numerical results obtained from this equation, as well as all the
information r>eeded to perform the calculations that cannot be found in Table
VII-1 can be found in Table VII-2.
A standard chi-square goodness of fit test is next used to compare the
observed and expected number of respiratory cancer deaths in the five cohorts.
Since two parameters I, 6 were estimated, the test had 5-2=3 degrees of
freedom associated with it. A chi-square value of 1.98 was obtained which has a
corresponding P~ 0.58 associated wi'th it indicating an excellent fit. We can
say that no other possible model could give a statistically significantly better
fit to the observed data than the one used here. Thus, until additional
information is obtained that is inconsistent with this model, the model will be
utilized to predict the respiratory cancer effects of coke oven emissions.
ESTIMATION OF THE UNIT RISK FOR COAL TAR PITCH VOLATILES
As part of the U.S. Environmental Protection Agency's Office of Air Quality
Planning and Standards program of regulating airborne carcinogens, a "unit risk"
is calculated for each suspect human carcinogen. The unit risk is defined as
the lifetime probability of cancer death due to a continuous exposure of 1
ugm/m^ of the agent for the entire lifespan.
To obtain a unit risk for coal tar pitch volatiles we note that the potency
155
-------
TABLE VI1-2. COMPARISON OF OBSERVED AND EXPECTED NUMBER OF RESPIRATORY CANCER DEATHS FOR RISK MODEL WHERE
MAXIMUM LIKELIHOOD ESTIMATES OF PARAMETERS ARE, I = 11.4, 6 = 9.7646 x 10~5
Age
Interval
18 - 29
30 - 39
40 - 49
50 - 59
>_ 60
0*/W*
3.5654 x 10'5
1.6212 x 10-4
7.8983 x 10-4
1.3683 x ID'3
4.8947 x 10-4
X2 =
3
Expected
GUI. 4) x 10-5 E(x,m) = WO*/W* +66(11.4)
0.2184 2.586
0.9194 10.802
1.2417 18.140
1.2583 18.228
0.2520 2.84
Z [0 - E(x,m)]2/E(x,m) = 1.98
all cohorts
P = 0.58
Observed
0
3
10
17
17
5
-------
parameter for 6 was in units of mg/m3 per working day. To convert this to
lifetime ugm/m3, we assume that a person works 240 days per year, 8 hours per
day, so that exposure would be 103 x (240/365) x (8/24) = 220 times as large
expressed in the new units. Thus, the potency parameters estimate is
6 (I0)/220 = 4.438 x 10'7.
To obtain a unit risk estimate under the same model as was fitted to the
coke oven workers, we assume that
x(v) = 1 v >_ 0
and
0 t-v < 11.4
w(t-v) =
1/R t-v >_ 11.4
so that
h2CX(t),t] = 4.438 x 10'7 x (t-11.4) t >_ 11.4 ' .
The risk we wish to calculate is to a "typical" U.S. inhabitant given a
specified exposure level. Thus, we set hi(t) equal to the death rates for all
causes for the total population for 5-year age groups found in the Vital
Statistics of the United States (U.S. Dept. of Health, Education, and Welfare
1977) and evaluate the integral of the function found by substituting the
required terms into the lifetime risk equation. This results in the
relationship
t
- [2.219xlO~7 x (t-11.4)2 + j> hi(v)dv]
P(co,l) = 6 4.438 x 10-7 x (t-11.4)e dt o
11.4
= 9.25 x 10-4
157
-------
For small exposures when x(v) = x, v ^ o, it follows that the lifetime risk
is
P(°°,x) = P(=°,l)x
Thus, for example, if the average increase in coal tar pitch volatiles in
the air due to coke oven emissions is 0.45 ug/m3, then an estimate of the
increase in the lifetime risk associated with such a lifetime exposure is
P(°°, 0.45) = 9.250 x 10~4 x 0.45 = 4.163 x 10~4
Estimation of Confidence Limits for the Unit Risk
The unit risk, as it is defined, is a function of two known parameters I, 6.
Under maximum likelihood theory, it is possible to obtain a joint confidence
region for the unknown parameters assuming that the underlying assumptions
utilized to obtain the likelihood are correct.
Once this confidence region is obtained, a confidence bound for the unit
risk is found by finding the maximum and minimum of all possible unit risks
computed from pairs of points contained within the joint confidence region.
The joint confidence region was generated in the following manner. First, a
fixed value I was selected and the unknown values 6*j found from the
relationship
-21n{L[5(I0),I0]/L(5*I, I)} =v22,l-a
158
-------
The term L[S(I0),I0] is the likelihood evaluated assuming that the
likelihood estimates are the true parameters and L(6*i, I) is the likelihood
evaluated at I and the two values 6*iu, ,!) lies within this interval with a
probability of 0.95 or more, or this statement may be written in the form
P (0.498 x 10-3 <_ p (ooj) £ 1.535 x 10~3} _> 0.95 .
It must be recognized that this confidence statement assumes that the
underlying cancer hypothesis is correct and only accounts for the statistical
imprecision in the estimation of the unknown parameters. The true value may,
with a probability that is unknown, be far beyond the region given above if some
of the underlying assumptions deviate considerably from reality.
Other potential sources of error are discussed in the next section.
159
-------
-------
-------
ADDITIONAL POTENTIAL PROBLEMS AND SOURCES OF ERROR ASSOCIATED WITH THE UNIT RISK
ESTIMATE
As noted, the confidence Interval that was generated for the unit risk
estimate is conditional upon: 1) the accuracy of the exposure estimates used in
the epidemic!ogical study, and, 2) the mathematical model used describing the
true biological dose-response.
A number of factors could make the estimated exposure inaccurate. First,
the samples taken around a single coke oven battery within a relatively short
time period are extrapolated into other locations and times in order to estimate
all of the workers total lifetime exposures. Also, there are several factors in
the sampling procedure that could seriously bias the results: Samples were
collected for as long a period as possible, i.e., until the personal-type
portable air pump's battery became exhausted or until the filter became so
clogged that the resistance was too great for the pump to overcome; average
sampling rates varied from 2.0 to 2.8 liters/min with total air volumes ranging
from 103 to 1200 liters; the moisture content of the air has a great effect on
the clogging of filters; improper seating of filter pads caused leakage around
the edges. All of these factors would tend to underestimate exposure which
would result in an overestimate of risk.
Some of the problems associated with the dose-response model are:
(1) Exposures were not uniform and over the maximum possible time frame as
was assumed.
(2) Cancer at sites other than the respiratory system was not considered.
(3) The response in nonwhite males was used to predict the response expected
in the population as a whole. If a synergistic effect existed between
some factor that is more common in the nonwhite lifestyle and coke oven
emissions, then an overestimate of risk would occur.
The extent and or plausibility of these factors being important is unknown
so that their influence on the precision of our estimate is pure conjecture at
this stage of knowledge.
162
-------
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