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                             DO NOT QUOTE OR CITE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/ ^~~-.-
                                      ii

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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
                                      iv

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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
                                       11

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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).
                                    14

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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.
                                      15

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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)
                               16

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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

-------
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

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    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

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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

-------
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

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              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

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            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

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                       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

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                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

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 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

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Figure V-5.  The effect of repeated exposure to 10 mg/m^  coal  tar  aerosol  on
             growth of rats.
             (MacEwen et al. 1976)
                                      61

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                   •.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

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(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)

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                                           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

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                                           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

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                                          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

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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

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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

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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

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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

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 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

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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

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   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

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    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

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      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

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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

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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

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    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

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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

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             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.

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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

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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

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             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

-------
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

-------
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
                                       98

-------
 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

-------
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.
                                      100

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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.
                                      104

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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

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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
                                     111

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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.
                                 115

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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
                                     120

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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.
                                     121

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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.
                                     123

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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
                                     124

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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.
                                     125

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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.
                                     126

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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.
                                     127

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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.
                                     143

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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.
                                     146

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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

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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

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    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

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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

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    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

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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

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     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

-------
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                                                           154

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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

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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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                              VIII.    REFERENCES
Andrews, L.S., B.R. Sonawane, and S.J.  Yaffe.   1976.   Characterization  and
    induction of aryl  hydrocarbon [benzo(a)pyrene]  hydroxylase in  rabbit bone
    marrow.  Res. Commun. Chem. Path.  Pharmacol.  15(2):319-339.

Autrup, H., C.C. Harris, G.D. Stoner,  J.K.  Selkirk, P.W.  Schaefer,  and  B.F.
    Trump.  1978.  Metabolism of [3H]benzo[a]pyrene by  cultured  human bronchus
    and cultured human pulmonary alveolar macrophages.   Lab.  Invest. 38(3):
    217-224.

Bast, R.C., Jr., T. Okuda, E. Poltkin,  R. Tarone,  H.J.  Rapp,  and H.V. Gelboin.
    1976.  Development of an assay for  aryl  hydrocarbon [benzo(a)pyrene]
    hydroxylase in human peripheral  blood monocytes.   Cancer  Res.  36:1967-1974.

Bend, J.R., Z. Ben-Zvi,  J. Van Anda, P.M. Dansette, and D.M.  Jerina.  1976.
    Hepatic and extrahepatic glutathione S-transferase  activity  toward  several
    arene oxides and epoxides in the rat.  In:   Polynuclear Aromatic
    Hydrocarbons:  Chemistry, Metabolism, and  Carcinogenesis, Vol.  1.
    Freudenthal, R.I., and P.W. Jones,  editors.   Raven  Press, New  York,  pp.
    63-75.

Bjorseth, A., 0. Bjorseth, and P.E.  Fjeldstad.   1978.   Polycyclic  aromatic
    hydrocarbons in the  work atmosphere.  II.   Determination  in  a  coke  plant.
    Scand. J. Work Environ. Health 4:224-236.

Bonser, Georgiana M. and M.D. Manch.   1932.  Tumors of  the  skin  produced  by
    blast-furnace tar.  Lancet 1:775-776.

Booth, J., G.R. Keysall, K. Pal, and P.  Sims.   1974.  The metabolism of
    polycyclic hydrocarbons by cultured  human  lymphocytes.  FEBS Lett.  43:341.

Boyland, E., and P. Sims.  1967.  The  carcinogenic  activities in mice of
    compounds related to benz[a]anthracene.   Int. J. Cancer 2:500-504.

Brookes, P.  1977.  Mutagenicity of polycyclic  aromatic hydrocarbons.   Mutat.
    Res. 39:257-284.

Carcinogen Assessment Group.  1980a.  The Carcinogen Assessment  Group's
    Carcinogenic Assessment of Toluene.   External Review  copy.   June 27,  1980.
    U.S. Environmental Protection Agency.  Unpublished.

Carcinogen Assessment Group (CAG).   1980b.   The Carcinogen  Assessment Group's
    List of Carcinogens.  July 14,  1980.  U.S.  Environmental  Protection Agency.
    Unpublished.

Casto, B.C., G.G. Hatch, S.L. Huang, J.L. Huisingh, S.  Nesnow, and M.D. Waters.
    1979.  Mutagenic and carcinogenic  potency  of  extracts of  diesel and  related
    environmental emissions:  In vitro mutagenesis  and  oncogenic
    transformation.  EPA International Symposium  on the Health Effects  of
    Diesel  Engine Emissions.  Cincinnati, Ohio.   pp. 843-859.
                                      163

-------
Casto, B.C., G.G. Hatch, and S.L.  Huang.   1980.   Confirmatory
    mutagenesis/carcinogenesis In  vitro blassasy of mobile  source  emissions  and
    comparative samples.  Report prepared by Northrop Services Inc.,  Research
    Triangle Park, NC for the U.S.  Environmental  Protection Agency's  Health
    Effects Research Laboratory, Research Triangle Park,  NC.   EPA  Contract No.
    68-02-2566.

Chiang, C.L.  1968.  Introduction  to stochastic  processes in biostatisties.
    John Wiley, New York.

Chuang, A.H.L., E.F. Howard, and E.  Bresnick.   1977.   Aryl  hydrocarbon
    hydroxylase in mouse mammary gland:   In vitro study using  mammary cell
    lines.  Chem. Biol.  Interact.  17:9-16.

Claxton, L.D.  1979a.  Data sheets  on "Coke oven (ambient)."   Sample  ID.
    GTPX-79-0003 Lab NSNC,  Strain TA 98.   Unpublished.  (April  19).

Claxton, L.D.  1979b.  Mutagenic and carcinogenic potency of diesel and  related
    environmental emissions:  Salmonella  bioassay.   Paper presented at the EPA
    International Symposium on the  Health Effects of Diesel  Engine Emissions.
    Cincinnati, Ohio.  (December).

Claxton, L., and J. Lewtas.  1981.   Data  supplied by  Office of Research  and
    Development Health Effects Research Laboratory  by Godlen Lewtas Huisingh.
    Unpublished.

Conn, J.A., A.P. Alvares, and A. Koppas.   1977.   On the occurrence of cytochrome
    P-450 and aryl hydrocarbon hydroxylase  activity in rat  brain.  J. Exp.
    Med. 145:1607-1611.

Ceilings, P.L.  1978.  Coke workers'  mortality:   a  nine year follow-up in  the
    British steel industry.  Report  prepared by  the Statistics  Branch, Institute
    of Occupational Medicine, Edinburgh,  Scotland,  for the  European Coal and
    Steel Community and  the British  Steel  Corporation.  Report No. TM/78/1.
    Unpublished.

Conney, A.H.  1967.  Pharmacological  implications of  microsomal enzyme
    induction.  Pharmacol.  Rev.  19:317.

Conney, A.H., J. Kapitulnik, W.  Levin,  P. Dansette,  and D.  Jerina.  1976.  Use
    of drugs in the evaluation of carcinogen metabolism in  man.  In:  Screening
    Tests in Chemical Carcinogenesis.   Montesano,  R.,  and L. Tomatis, editors.
    Lyon, France:  IARC,  IARC Publ.  No.  12, pp.  319-336.

Conney, A.H., E.J. Pantuck, K.C. Hsiao, A.P. Alvares,  and A. Kappas.  1977.
    Regulation of drug metabolism in  man  by environmental chemicals and  diet.
    Fed. Proc. 36(5):1647-1652.

Coy, D.W., C.C. Allen, and  B.H.  Carpenter.   1980.   Research Triangle  Institute,
    Research Triangle Park, N.C. Preliminary  Environmental  Assessment on
    Formcoke Cokemaking  Process. Prepared  for Industrial Environmental  Research
    Laboratory, U.S. Environmental Protection  Agency.  Contract No. 68-02-3170,
    Task 17, June 1980.
                                      164

-------
Curren, R.D., R.E.  Kouri,  C.M.  Kim,  and L.M.  Schechtman.   1979.  Mutagenic  and
    carcinogenic potency of extracts from diesel  related  environmental
    emissions:   Simultaneous morphological  transformation and mutagenesis in
    BALB/c 3T3  cells.  Paper presented at the EPA International  Symposium on the
    Health Effects  of Diesel Engine  Emissions.   Cincinnati,  Ohio.   December
    1979.  pp.  861-872.

Davies, G.M.  1977.  A mortality study of coke oven  workers  in two  South Wales
    integrated steelworks.  Br. J.  Ind. Med.  34:291-297.

Davies, G.M.  1978.  Erratum.  Br. J.  Ind.  Med.  35:176.

Dent, J.G.  1979.  Choice of activating systems  for  in  vitro mutagenesis assays.
    In: Mammalian cell mutagenesis:  The maturation oT~test systems,  Hsie, A.W.,
    J.P. O'Neill, V.K. McElheny, eds.   Cold Spring Harbor Conference.

Doherty, J.D.,  and J.A. Decarlo.  1967.  Coking  practice  in  the  United  States
    compared with some western  European practices.  Blast Furnace and Steel
    Plant.  February 1967.  pp. 141-152.

Doll, R., R.E.W. Fisher, E.J. Gammon,  W. Gunn,  G.O.  Hughes,  F.H. Tyrer, and VI.
    Wilson.  1965.   Mortality of gasworkers with special  reference  to cancers of
    the lung and bladder,  chronic bronchitis, and pneumoconiosis.   Br.  J. Ind.
    Med. 22:1-12.

Driesbach, R.H.  1977.  Handbook of  poisoning.   Lange Medical Publications.  Los
    Altos, CA.   Ninth Edition.

Epler, J.L., W. Winton, T. Ho,  F.W.  Larimer,  T.K. Rao,  A.A.  Hardigree.  1977.
    Comparative mutagenesis of  quinolines.   Mutat. Res. 39:285-296.

Epler, J.L., T.K. Rao, and M.R. Guerin.  1979.   Evaluation of feasibility of
    mutagenic testing of shale  oil  products and effluents.  Environ. Health
    Perspect. 30:179-184.

Epler, J.L., W. Winton, A.A. Hardigree, F.W.  Larimer.  1980. The appropriate
    use of genetic toxicology in industry.  In:  The scientific basis of  toxicity
    assessment.  Elsevier/North-Holland Biomed.  Press,  H. Witschi,  ed.

Freudenthal, R.I.,  S.G. Hundley, and S.M. Cottaneo.   1978.  A comparison of the
    metabolites of benzo[a]pyrene by lung mixed function  oxidase from rat,
    rhesus, and humans.  In:  Carcinogenesis, Vol. 3. Polynuclear Aromatic
    Hydrocarbons.  Freudenthal, R.I.,  and P.W.  Jones, editors.   Raven Press.
    New York.

Gail, M.  1975.  Measuring the  benefit of reduced exposure to environmental
    carcinogens.  J. Chronic. Dis.  28:135-147.

Gelboin, H.V.,  N. Kinoshita, andF.J.  Wiebel.  1972. Microsomal hydroxylase:
    Studies on the mechanism of induction and their  role  in  polycyclic
    hydrocarbon action.  In:  Collection of Papers Presented at  the Annual
    Symposium on Fundamental Cancer Research, Series 24.   pp. 211-224.
                                      165

-------
Gibb, H.  1978a.  Phone conversation of April  25,  1978 with J.D.  MacEwen
    (University of California) on test results of  monkeys  and rabbits  in  MacEwen
    et al. study.

Gibb, H.  1978b.  Phone conversation of May 8, 1978 with David Groth
    (NIOSH-Cincinnati) on test results of rabbits  and monkeys from  MacEwen
    (1976) study.

Gibb, H.  1981.  Phone conversation of July 28,  1981 with  William Wagoner
    (NIOSH-Cincinnati) on disposition of monkeys from MacEwen et  al.  (1976)
    study.

Goldstein, E., F. Goldstein,  N.F. Peek, and N.J. Parker.   1980.   Absorption  and
    transport of nitrogen oxides.  In:  Nitrogen  Oxides and their  effects  on
    health.  S.D. Lee, Ed.  Ann Arbor Science  Publishers,  Inc.  Ann Arbor, MI.

Grundin, R., S. Jakobsson, and D.L.  Cinti.   1973.   Induction of microsomal aryl
    hydrocarbon (3,4-benzo[a]pyrene) hydroxylase and cytochrome P-450K  in rat
    cortex.  I.  Characteristics of the hydroxylase system.   Arch.  Biochem.
    Biophys. 158(2):544-555.

Hass, Bruce S., Emily E.  Brooks, Karen E.  Schumann, and Suzanne S.  Dornfeld.
    1981.  Synergistic, additive, and antagonistic mutagenic responses  to binary
    mixtures of benzo[a]pyrene and benzo[e]pyrene  as detected by  strains  TA98
    and TA100 in the Salmonella/microsome assay.  Environmental Mutagenesis
    3:159-166.

Hoffman, D., I. Schmeltz, S.S. Hecht,  and E.L. Wynder.   1978.   Tobacco
    carcinogenesis.   In:   Polycyclic Hydrocarbons  and Cancer.   Gelboin, H.V.,
    and P.  Ts'o, editors.  Academic  Press,  New York,  pp. 85-114.

Hogan, W.T., and F.T. Koelble, Industrial  Economics Research Institute, Fordham
    Univ.  1979.  Analysis of the U.S.  metallurgical  coke  industry.  Prepared
    for U.S. Dept. of Commerce,  Economic Development Administration and Lehigh
    Univ.  EDA Project No. 99-26-09886-10.

Hollstein,  Monica, Joyce  McCann, Frank A.  Angelosanto,  and Warren W. Nichols.
    1979.  Short-term tests for carcinogens and  mutagens.   Mutat. Res.
    65(3):133.

Horton, W.A.  1961.   An investigation  of the carcinogenic  properties of various
    coal  tars of commercial  fractions  thereof.  Report of  the Kettering
    Laboratory, Department of Preventive Medicine  and Industrial  Health.
    Cincinnati: University of Cincinnati,  32 pp.

Horton, A.W., R. Tye, and K.L. Stemmer.   1963.  Experimental  carcinogenesis of
    the lung.  Inhalation of  gaseous formaldehyde  or an aerosol of  coal tar by
    C3H mice.  J. Natl. Cancer Inst.  30(l):31-43.
Hueper, W., and W.W.  Payne.   1960.   Carcinogenic studies on  petroleum asphalt,
    cooling oil, and  tar.  Archives  of Pathology 70:372-384.

Huisingh, J. (Lewtas).  1981.  Memo  of October 27,  1981 to Mr. Herman Gibb,
    Carcingen Assessment  Group entitled "Review  of the Carcinogen Assessment of
    Coke Ovens Draft  Document."   Unpublished.
                                      166

-------
Huisingh, J.L., R.L. Bradow, R.H. Jungers, B.D. Harris, R.B. Zweidinger,  K.M.
    Gushing, D.E. Gill, and R.E. Albert.  1979.  Mutagenic and carcinogenic
    potency of extracts of diesel and related environmental  emissions:   Study
    design, sample generation, collection, and preparation.   Paper presented at
    the EPA International Symposium on the Health Effects of Diesel Engine
    Emissions.  Cincinnati, Ohio.  December 1979.

IARC (International Agency for Research on Cancer).  1973.  IARC Monographs on
    the Evaluation of the Carcinogenic Risk of Chemicals to  Humans.  Vol.  2.
    Some inorganic and organometallic compounds.  Lyon, France.

IARC (International Agency for Research on Cancer).  1974.  IARC Monographs on
    the Evaluation of the Carcinogenic Risk of Chemicals to  Humans.  Vol.  4.
    Some aromatic amines, hydrazine, and related substances, n-nitroso
    compounds, and miscellaneous alkylating agents.  Lyon, France.

IARC (International Agency for Research on Cancer).  1976.  IARC Monographs on
    the Evaluation of the Carcinogenic Risk of Chemicals to  Humans.  Vol.
    11.  Cadmium, nickel, some epoxides, miscellaneous industrial  chemicals, and
    general considerations on volatile anaesthetics.   Lyon,  France.

IARC (International Agency for Research on Cancer).  1979.  IARC Monographs on
    the Evaluation of the Carcinogenic Risk of Chemicals to  Humans.  Chemicals
    and industrial processes associated with cancer in humans.  IARC Monographs
    Supplement 1, 1979.  Lyon, France.

Jerina, D.M. and J.W. Daly.  1974.  Arene oxides:  A new aspect of drug
    metabolism.  Science 185(4151):573-582.

Jerina, D.M., R.E. Lehr, H. Yarn', 0. Hernandez, P.M.  Dansette, P.6. Wislocki,
    A.W. Wood, R.L. Change, W. Levin, and A.H. Conney.  1976.   Mutagenicity of
    benzo[a]pyrene derivatives and the description of a quantum mechanical  model
    which predicts the ease of carbonium ion formation from  diol  epoxides.   J_n
    vitro metabolic activation in mutagenesis testing,  de Serres, F.J.,
    J.R. Fouts, J.R. Bend, and R.M. Philpot, editors.  Amsterdam,
    Elsevier/North-Holland Biomedical Press, pp. 159-177.

Jerina, D.M., R.  Lehr, M. Schaefer-Ridder, H. Yagi, J.M. Karle, D.R.  Thakker,
    A.W. Wood, A.Y.H. Leu, D. Ryan, S. West, W. Levin, and A.H. Conney.   1977.
    Bay-region epoxides of dihydrodiols:  A concept explaning  the  mutagenic and
    carcinogenic  activity of benzo[a]pyrene and benzo[a]anthracene.  In:
    Origins of Human Cancer.  Book B. Mechanisms of Carcinogenesis.  Volume 4.
    H.H. Hiatt, J.D. Watson, and J.A. Winsten, eds.  Cold Spring Harbor
    Laboratory,  pp. 639-658.

Jerina, D.M., J.M. Sayer, D.R. Thakker, H. Yagi, W. Levin, A.W. Wood, and  A.H.
    Conney.  1980.  Carcinogenic!'ty of polycyclic aromatic hydrocarbons:   The
    bay-region theory.  In:  Carcinogenesis:  Fundamental  Mechanisms and
    Environmental  Effects.  B. Pullman, P.O.P. Ts'o,  and H.  Gelboin,  Eds.  D.
    Reidel  Publishing Company.  Boston,  pp. 1-12.
                                      167

-------
Jungers, R., R. Burton,  L.  Claxton,  and J.  Lewtas  Huising.   1980.   Evaluation of
    collection and extraction methods  for mutagenesis  studies on ambient air
    particulate.  Pages  45-65 in M.D.  Waters,  S.S.  Sandhu, J. Lewtas Huisingh,
    L. Claxton, and S. Nesnow, eds.  Short-term bioassays in analysis of complex
    environmental  mixtures.   M.D.  Waters, S.S. Sandhu, J. Lewtas Huisingh, L.
    Claxton, and S. Newnow.   Plenum  Press,  New York, N.Y. u

Kaden, D.A., R.A.  Hites, and W.G.  Thelly.   1979.   Mutagenicity of  soot and
    associated polycyclic aromatic hydrocarbons of Salmonella typhimurium.
    Cancer Res. 39:4152-4159.

Kapitulnik, J., W. Levin, A.M. Conney,  H. Yagi, and D.M. Jerina.   1977.
    Benzo[a]pyrene 7,8-dihydrodiol  is  more  carcinogenic than benzo[a]pyrene in
    newborn mice.   Nature.  266:378-380.

Kapitulnik, J., P.G. Wislocki, W.  Levin, H.  Yagi,  D.R. Thakker, H.  Akagi, M.
    Koreeda, D.M.  Jerina, and A.M.  Conney.   1978a.  Marked differences in the
    carcinogenic activity of optically  pure ( + )- and  (-)-trans-7,8-dihydroxy-
    7,8-dihydrobenzo[a]pyrene in newborn mice.  Cancer Res.  38:2661-2665.

Kapitulnik, J., P.G. Wislocki, W.  Levin, H.  Yagi,  D.M. Jerina, and A.M. Conney.
    1978b.  Tumorigenicity studies with diol-epoxides  of benzo[a]pyrene which
    indicate that (+)-trans-7b-8a-dihydroxy-9alOa-epoxy-7,8,9,10-
    tetrahydro-benzo[a]pyrene is an  ultimate carcinogen in newborn mice.  Cancer
    Res. 38:354-358.

Kawai, M., H. Amamoto,  and K. Harada.   1967.  Epidemiologic  study  of
    occupational lung cancer.  Arch. Environ.  Health 14:859-864.

Kew, Gregory (EPA).  1981.   Memo of August  12, 1981 to Vicki Vaughan-Dellarco
    (EPA) on a report entitled "Support of  a study to  evaluate the effect of
    ozone generated by  a masssive volume sampler on the mutagenic  activity to
    samples collected for bioassay."   Unpublished.

Kimball, R.F., and N.B.  Munro.  1981.   A critical  review of  the mutagenic and
    other genotoxic effects of direct  coal  liquefaction.  Oak Ridge National
    Laboratory, Oak Ridge,  Tennessee.   Contract No. W-7405-eng-26.  July 1981.

Kimura, T., M. Kodama,  and C. Nagata.   1977.  Difference in  benzo[a]pyrene
    metabolism between  lung and liver  homogenates.  Biochem. Pharmacol.
    26:671-674.

Kinkead, E.R.  1973.  Toxicity of coal  tar  aerosol, in Proceedings of  the Fourth
    Annual Conference of Environmental  Toxicology,  Fairburn, OH:   October 16-18,
    pp. 177-188.

Land, C.E.  1976.  Presentation at OSHA hearings on coke oven standards.

Lao, R.C., R.S. Thomas,  and J.L. Minkima.   1975.   Computerized gas
    chromatography mass  spectrometric  analysis of  polycyclic samples.  J.
    Chromatogr. 112:681-700.
                                      168

-------
Leber, P., G. Kerchner, and R.I. Freudenthal.   1976.  A comparison of
    benzo[a]pyrene metabolism by primates, rats, and miniature swine.
    In:  Carcinogenesis, Vol. 1:  Polynuclear Aromatic Hydrocarbons:   Chemistry,
    Metabolism, and Carcinogenesis.  Freudenthal, R.I., and P.W.  Jones,
    editors.  Raven Press, New York, pp. 35-43.

Lehr, R.E., H. Yagi, D.R. Thakker, W. Levin, A.W. Wood, A.H. Conney,  and D.M.
    Jerina.  1978.  The bay region theory of polycyclic aromatic
    hydrocarbon-induced carcinogenicity.  In:   Carcinogenesis, Vol. 3:
    Polynuclear Aromatic Hydrocarbons.  Freudenthal, R.I., and P.W. Jones,
    editors, Raven Press, New York, pp. 231-241.

Levin, W., A.W. Wood, H. Yagi, P.L.M. Dansette, D.M. Jerina, and  A.H. Conney.
    1976.  Carcinogenicity of benzo[a]pyrene 4,5-, 7,8-, snf 9,10-oxides on
    mouse skin.  Proc. Natl. Acad. Sci. USA 73(l):243-247.

Levin, W., A.W. Wood, P.G. Wislocki, J. Kapitulnik, H. Yagi, D.M. Jerina,  and
    A.H. Conney.  1977.  Carcinogenicity of benzo-ring derivatives of
    benzo[a]pyrene on mouse skin.  Cancer Res. 37:3356-3361.

Lloyd, J.W.  1971.  Long-term mortality study  of steel workers.
    V. Respiratory cancer in coke plant workers.  J. Occup. Med.  13(2):53-68.

Lloyd, J.W.  1974.  Study of long-latent disease in industrial populations.
    Journal of the Washington Academy of Science 64(2):135-144.

Lloyd, J.W., and A. Ciocco.  1969.  Long-term  mortality study of
    steel workers.  I. Methodology.  J. Occup.  Med. 11(6):299-310.

Lloyd, J.W., F.E. Lundin, Jr. C.K. Redmond,  and P.B. Geiser.  1970.
    Long-term mortality study of steelworkers.  IV. Mortality by  work area.
    J. Occup. Med.  12(5):151-157.

Lu, A.Y.H., W. Levin, P.E. Thomas, D.M. Jerina, and A.H. Conney.   1978.
    Enzymological properties of purified liver microsomal  cytochrome  P-450
    system and epoxide hydrase.   In:  Carcinogenesis, Vol. 3:   Polynuclear
    Aromatic Hydrocarbons.  Freudenthal, R.I., and P.W. Jones, editors.   Raven
    Press, New York, pp. 243-252.

MacEwen, James D., and E.H. Vernot.  Toxic Hazards Research Unit  Annual
    Technical Report: 1972, 1973, 1974, 1975,  1976.  Ohio: Aerospace  Medical
    Research Laboratory, Wright-Patterson Air  Force Base.

MacEwen, J.D., A. Hall  III, and L.D. Scheel.  1976.  Experimental  oncogenesis in
    rats and mice exposed to coal tar aerosols.  Presented before the Seventh
    Annual Conference on Environmental Toxicology, Dayton, OH. AMRL  Technical
    Report No. 76-125.   October.  16 pp.

Magee, P.N., R.  Montesano and R. Preussmann.  1976.  N-nitroso compounds and
    related carcinogens.  In Chemical  carcinogens (ed. C.E. Searle),  Monograph
    173, pp. 491.  Amercian Society, New York.

Mancuso, Thomas F.  1977.   Lung cancer among black migrants.   Journal  of
    Occupational  Medicine 19(8):531-532.
                                      169

-------
Mancuso, Thomas F., and Theodor D. Sterling.  1974.   Relation of place of birth
    and migration in cancer mortality in the U.S.-a  study of Ohio residents
    (1959-1967).  Journal of Chronic Diseases 27:459-474.

Marquardt, H.  1976.  Microsomal metabolism of chemical  carcinogenis in animals
    and man.  In:  Screening Tests in Chemical  Carcinogenesis.   Montesano,  R.5
    and L. Tomatis, editors.  International Agency for Research on Cancer,  Lyon,
    France, IARC Publication No. 12, pp. 309-328.

Mazumdar, S., C. Redmond, W. Sollecito,  and N.  Sussman.   1975.   An
    epidemiological study of exposure to coal-tar-pitch volatiles among coke
    oven workers.  APCA J.  25(4):382-389.

McCann, J., N.E. Spingarn,  J. Kabori, and B.N.  Ames.   1975a.   Detection of
    carcinogens as mutagens:  Bacterial  tester strains within R factor plasmids.
    PNAS (USA) 72:979-983.

McCann, 0., E. Choi, E. Yamasaki,  and B.N.  Ames.   1975b.   Detection of
    carcinogens as mutagens in the Salmonella/microsome test:   Assay of 300
    chemicals.  Proc.  Nat.  Acad. Sci. USA 72:5135-5139.

McConnell, E.E. and H.D. Specht.  1973.   Lesions  found in animals exposed to
    coal tar aerosols.  In:   Proceedings of the Fourth Annual  Conference on
    Environmental Toxicology, Fairburn,  OH.  October  16-18,  Paper No.  14,  pp.
    189-198.

Mitchell, A.D.  1981.   Data supplied by  Jo  Ellen  Lewtas,  Office of Research and
    Development, Health Effects Research Laboratory,  Research Triangle Park,
    NC.  Unpublished.

Mitchell, A.D., E.L. Evans,  M.M. Jotz, E.S. Riccio, K.E.  Mortelmans,  and V.F.
    Simmon.  1979.  Mutagenic and  carcinogenic  potency of extracts of  diesel and
    related environmental emissions:   In Vitro  mutagenesis and  DNA damage.
    Paper presented at the  EPA International  Symposium on the Health Effects of
    Diesel Emissions.   Cincinnati, Ohio.  December 1979.

Moller, M., and E. Dybing.   1980.   Mutagenicity studies  with  urine concentrates
    from coke plant workers.  Scand.  J.  Work,  environ,  health 6:216-220.

Mortelmans, K.E., E.S. Riccio,  and W.  Tanaka.   1980.   In  vitro  microbiological
    mutagenicity assays of  2-nitro flourene,  benzo[a]pyrene,  and diesel  samples
    preincubation assay. Prepared by Stanford  Research  Institute,  Palo Alto,
    California for the U.S.  Environmental Protection  Agency,  Research  Triangle
    Park, N.C.  EPA Contract No. 68-02-1947.   Unpublished.

National Research Council.   1981.   Aromatic amines:   An  assessment of  the
    biological and environmental effects.   Committee  on  Amines.   Board on
    Toxicology and Environmental Health  Hazards.   Assembly of Life Sciences.
    National  Research  Council.   National  Academy Press.   Washington, D.C.

Nebert, D.W.  and J.S.  Felton.  1976.   Importance of genetic  factors influencing
    the metabolism of  foreign compounds.  Fed.  Proc.  35:1133-1141.
                                      170

-------
Nesnow, S.  1980.  Report on skin tumorigenesis studies of diesel  emissions
    and related samples on C57 black mice.  Unpublished.

Nesnow, S., L. Evans, A. Stead, J. Creason, T.J. Slaga, and L.L. Triplett.
    1981.  Skin carcinogenesis studies of emission extracts.  In:  lexicological
    effects of emissions from diesel engines.  J. Lewtas, ed.  Elsevier North
    Holland, Inc.  New York.  In press.

NIOSH (National Institute for Occupational Safety and Health).  1978.  Criteria
    for a recommended standard...occupational exposure to coal tar products.
    DHEW Publication No. (NIOSH) 78-107.   U.S. Dept. of Health, Education,  and
    Welfare, Public Health Service, Center for Disease Control.

OSHA (Occupational Safety and Health Administration).  1976.  Final
    environmental impact statement.  Coke oven emissions.  U.S. Dept. of Labor.
    August 1976.

Pelkonen, 0.  1976.  Metabolism of benzo[a]pyrene in human adult and fetal
    tissues.   In:  Carcinogenesis, Vol. 1:  Polynuclear Aromatic Hydrocarbons:
    Chemistry, Metabolism, and Carcinogenesis.  Freudenthal, R.I., and P.W.
    Jones, editors.  Raven Press, New York, pp. 9-21.

Pelroy, R.A., and M.R. Peterson.  1979.  Use of Ames test in evaluation of shale
    oil fractions.  Environ. Health Perspect. 39:191-203.

Rao, K.I., J.A. Young, A.A. Hardigree, W. Winton, and J.L. Epler.   1978.
    Analytical and biological analyses of test materials from the synthetic
    fuel technologies.  II.  Extended genetic and biochemical studies with
    mutagenic  fractions.  Mutat. Res. 54:185-191.

Rao, T. Kameswar, J.A. Young, C.E. Weeks, T.J. Slaga, and J.L. Epler.  1979.
    Effect of the co-carcinogen benzo[e]pyrene on microsome-mediated chemical
    mutagens in Salmonella typhimurium.  Environmental mutagenesis 1:105-112.

Redmond, C.K.  1976.  Epidemiological studies of cancer mortality in coke
    plant workers.  Presented at the Seventh Annual Conference on Environmental
    Toxicology, Dayton, OH.  October 13-15.

Redmond, C.  1981.  Personal communication of October 21, 1981 to Mr. Herman
    Gibb, Carcinogen Assessment Group, Office of Research and Development,  U.S.
    Environmental Protection Agency.

Redmond, C.K., A. Ciocco, J.W. Lloyd, and H.W. Rush.  1972.   Long term
    mortality  study of steelworkers.  VI.  Mortality from malignant neoplasms
    among coke oven workers.  J. Occup. Med. 14:621-629.

Redmond, C.K., B. R. Strobino, and R. H.  Cypress.   1976.  Cancer experience
    among coke by-product workers.  Ann.  N.Y. Acad. Sci. 271:102-115.

Redmond, C., H.S. Wieand, H.E. Rockette,  R. Sass, and G. Weinberg.  1979.
    Long-term mortality experience of steelworkers.  Report  prepared by the
    University of Pittsburgh Graduate School of Public Health, Pittsburgh,
    Pennsylvania, for the National  Institute for Occupational Safety and
    Health, Division of Surveillance, Hazard Evaluation, and  Field Studies.
    Cincinnati, Ohio.  Contract No. HSM-99-71-32.
                                      171

-------
Reid, D.D. and C.  Buck.   1956.   Cancer  in  coking  plant workers.  Br. J. Ind.
    Med. 13:265-269.

Reznikoff, C.A.,  D.W.  Brankow,  and  C. Heidelberger.  1973.  Establishment and
    characterization  of  a cloned line of C3H mouse embryo cells sensitive to
    post-confluence inhibition  of cell  division.  Cancer Res. 33:3231-3238.

Roy, A.B., and P.A. Trudinger.   1970.   The metabolism in animals of inorganic
    sulphur compounds.   In:   The Biochemistry  of  Inorganic Compounds of Sulphur.
    Cambridge University Press.   Great  Britain.

Sakabe,  Hiroyuki,  Kenzaburo  Tsuchiya, Nobolru  Tahekura, Shigeru Nomura, Shigezi
    Koshi, Kazuo  Takemoto, Hidetsuru Matsuskita,  and Yukio Matsuo.  1975.  Lung
    cancer among  coke  oven workers  - A  Report  to  Labour Standard Bureau,
    Ministry of Labour,  Japan.   Industrial Health.  13:57-68.

Santodonato, J.,  and  P.M. Howard.   1981.   Azaarenes:  Sources, distribution,
    environmental  impact, and health effects.  Hazard Assessment of Chemicals.
    Current Developments. Vol.  1. 421-440.

Sasmore, D.P.  1976.   Histopathologic evaluation  of animal tissues from coal tar
    studies (rat,  rabbit, hamster,  and  mouse).  Performed under NIOSH Contract
    No.  210-75-0050.   Unpublished.

Selkirk, J.K., E.  Huberman,  C.  Heidelberger.   1971.  An epoxide is an
    intermediate  in the  microsomal  metabolism  of  the chemical carcinogen,
    dibenz[a,h]anthracene.   Biochem. Biophys.  Res. Commun. 43(5):1010-1016.

Selkirk, J.K., R.G. Croy, P.P.  Roller,  and H.V. Gelboin.  1974.  High pressure
    liquid chromatographic analysis fo  benzo[a]pyrene metabolism and covalent
    binding and the mechanism of action of 7,8-benzoflavone and
    l,2-epoxy-3,3,3-trichloropropane.   Cancer  Res. 34:3473-3480.

Selkirk, J.K., R.G. Croy, J.P.  Jr.  Whitlock, and  H.V. Gelboin.  1975.  In vitro
    metabolism of benzo[a]pyrene by human  liver microsomes and lymphocytes.
    Cancer Res. 35:3651-3655.

Selkirk, J.K., S.K. Yang, and H.V.  Gelboin.  1976.  Anaylsis of benzo[a]pyrene
    metabolism in human  liver and lymphocytes  and kinetic anaylsis of
    benzo[a]pyrene in  rat liver microsomes.  In:  Carcinogenesis, Vol. 1:
    Polynuclear Aromatic Hydrocarbons:  Chemistry, Metabolism, and
    Carcinogenesis.  Freudenthal, R.I., and P.M.  Jones, editors.  Raven Press,
    New York, pp.  153-169.

Sims, P.  1970.  Qualitative and quantitative  studies on the metabolism of a
    series of polycyclic aromatic hydrocarbons by rat-liver preparations.
    Biochem. Pharmacol.  19:795.

Sims, P.  1976.  The  metabolism of  polycyclic  hydrocarbons to dihydrodiols and
    diol epoxides by  human and  animal tissues.  In:  Screening Tests in Chemical
    Carcinogenesis.  Montesano,  R., H.  Bartsch, and L. Tomatis, editors.
    IARC.  Lyon,  France. IARC Publication  No.  12, pp. 211-224.
                                      172

-------
Sims, P. and P.L. Grover.  1974.  Epoxides in polycyclic aromatic hydrocarbon
    metabolism and carcinogenesis.  Adv.  Cancer Res.  20:165-274.

Stanford Research Institute.  1978.  Final report by  E.B.  Suta (revised May
    1979).  Human population exposures to coke oven atmospheric emissions.

Stead, A.G., V. Hasselblad, J.P. Creason, and L.  Claxton.   1981.   Modeling  the
    Ames test.  Mutat. Res. 85:13-27.

Stoming, T.A., W. Bornstein, and E. Bresnick.  1977.   The  metabolism of
    3-methylcholanthrene by rat liver microsomes - A  reinvestigation.   Biochem.
    Biophys. Res. Commun. 79(2):461-469.

Strup, Paul E., and A. Bjorseth.  1979.   Final  report on artifact formation in
    Battelle megavolume sampler.  Submitted to U.S. Environmental  Protection
    Agency, Research Triangle Park, NIC under Contract No.  68-02-2454,  Task  No. 8
    (July 18).

Tokiwa, H., Fukuoka Environmental  Research Center, Fukuoka 818-01,  Japan.   1981.
    Letter to Dr. Vicki Vaughan-Dellarco, Reproductive Effects Assessment Group,
    U.S. Environmental Protection Agency.  Unpublished.

Tokiwa, H., K. Morita, H. Takeyoshi, K.  Takahashi, and Y.  Ohnishi.   1977.
    Detection of mutagenic activity in particular air pollutants.   Mut.  Res.
    48:237-248.

Thakker, D.R., H. Yagi, H. Akagi,  M. Koreeda, A.Y.H.  Lu, W.  Levin,  A.W.  Wood,
    A.H. Conney, and D.M. Jerina.   1977.   Metabolism  of benzo[a]pyrene.  VI.
    Stereoselective metabolism of benzo[a]pyrene and  benzo[a]pyrene
    7,8-dihydrodiol  to diol epoxides.  Chem.  Biol. Interact.  16:281-300.

Thakker, D.R., W. Levin, A. Stoming, A.H. Conney,  and D.M. Jerina.   1978.
    Metabolism of 3-methylcholanthrene by rat liver microsomes and  a highly
    purified monooxygenase system with and without epoxides  hydrase.   In:
    Carcinogenesis,  Vol. 3:  Polynuclear Aromatic  Hydrocarbons.   Freudenthal,
    R.I., and P.W. Jones, editors.  Raven Press,  New  York, pp.  253-264.

Tye, R., and K.L. Stemmer.  1967.   Experimental  carcinogenesis of the  lung.  II.
    Influence of phenols in the production of carcinoma.  J.  Nat!.  Cancer
    Inst. 39:175-186.

U.S. Department of Health, Education and  Welfare.   1977.  Vital  statistics  of
    the United States.  Vol. II. Mortality,  Part A.  U.S.  Government Printing
    Office.  017-022-00549-2.

U.S. EPA (U.S. Environmental Protection  Agency).   1977a.  Toxicology of  metals.
    Vol. II.  U.S. EPA Report No.  EPA-600/1-77-022, May  1977.

U.S. EPA (U.S. Environmental Protection  Agency).   1977b.  Sampling  and analysis
    of coke oven-door emissions.  U.S.  EPA,  Office of Research and  Development,
    Research Triangle Park, N.C. 27711.   Report No. EPA-600/2-77-213.  October
    1977.
                                      173

-------
U.S. EPA (U.S. Environmental  Protection  Agency).   1978a.   An  assessment of  the
    health effects of coke oven  emissions.  U.S. EPA,  Office of Research and
    Development, Washington,  DC.   April  1978.

U.S. EPA (U.S. Environmental  Protection  Agency).   1978b.   Reviews  of  the
    environmental  effects of  pollutants:   III.  Chromium.  U.S. EPA,  Office of
    Research and Development.   Report No.  EPA-600/1-78-023.   May 1978.

U.S. EPA (U.S. Environmental  Protection  Agency).   1978c.   An  assessment of
    health effects of benzene  germane to low  levels of exposure.   U.S. EPA,
    Office of Health and Ecological  Effects.   Report  No. EPA-600/1-78-061.
    September 1978.

U.S. EPA (U.S. Environmental  Protection  Agency).   1979.  Health assessment
    document for polycyclic organic  matter.   Environmental Criteria and
    Assessment Office,  Office  of  Health  and Environmental  Assessment, Office of
    Research and Development,  U.S. Environmental  Protection Agency, Research
    Triangle Park, NC.   Report No. EPA 600/9-79-008.

U.S. EPA (U.S. Environmental  Protection  Agency).   1980a.   Health assessment
    document for polycyclic organic  matter.   U.S.  EPA, Office of Research and
    Development, Washington,  DC.   External  Review Draft No. 2.  June  1980.

U.S. EPA (U.S. Environmental  Protection  Agency).   1980b.   Ambient  water quality
    criteria for benzene.  U.S.  EPA,  Office of Water  Regulations and  Standards.
    Criteria and Standards Divisions.  Report No.  EPA 440/5-80-018.   October
    1980.

U.S. EPA (U.S. Environmental  Protection  Agency).   1980c.   Ambient  water quality
    criteria for phenol.   U.S.  EPA Office  of  Water Regulations and Standards.
    Criteria and Standards Division.   Report  No.  EPA  440/5-80-066.  October
    1980.

U.S. EPA (U.S. Environmental  Protection  Agency).   1980d.   (ortho,  meta, para)-
    Xylene:  Hazard Profile.   U.S. EPA Environmental  Criteria and  Assessment
    Office.  Office of Research  and  Development.   Cincinnati, Ohio.   Jan. 31,
    1980.  Unpublished.

U.S. EPA (U.S. Environmental  Protection  Agency).   1980e.   Ambient  water quality
    criteria for arsenic.  U.S.  EPA  Office of Water Regulations and Standards.
    Criteria and Standards Division.   Report No.  EPA 440/5-80-021.   October
    1980.

U.S. EPA (U.S. Environmental  Protection  Agency).   1980f.   Ambient  water quality
    criteria for beryllium.  U.S.  EPA Office  of Water Regulations  and Standards.
    Criteria and Standards Division.   Report No.  EPA 440/5-80-024.   October
    1980.

U.S. EPA (U.S. Environmental  Protection  Agency).   1980g.   Ambient  water quality
    criteria for Chromium. U.S.  EPA Office of Water  Regulations and  Standards.
    Criteria and Standards Division.   Report No.  EPA 440/5-80-024.   October
    1980.
                                      174

-------
U.S. EPA (U.S. Environmental Protection Agency).   1980h.   Ambient water
    quality criteria for cadmium.  U.S. EPA Office of Water Regulations and
    Standards.  Criteria and Standards Division.    Report No.  EPA 440/5-80-025.
    October 1980.

U.S. EPA (U.S. Environmental Protection Agency).   1980i.   Ambient water quality
    criteria for nickel.  U.S. EPA Office of Water Regulations and Standards.
    Criteria and Standards Division.    Report No.  EPA 440/5-80-060.   October
    1980.

U.S. EPA (U.S. Environmental Protection Agency).   1980j.   Ambient water quality
    criteria for selenium.  U.S.  EPA Office of Water Regulations and Standards.
    Criteria and Standards Division.    Report No.  EPA 440/5-80-070.   October
    1980.

U.S. EPA (U.S. Environmental Protection Agency).   1980k.   Ammonia:  Hazard
    Profile.  U.S. EPA Environmental  Criteria and  Assessment Office, Office of
    Research and Development, Cincinnati, Ohio.   April  15, 1980.  Unpublished.

U.S. EPA (U.S. Environmental Protection Agency).   19801.   Air  quality criteria
    for carbon monoxide.  U.S. EPA Environmental  Criteria and  Assessment Office,
    Office of REsearch and Development, Research  Triangle Park,  NC.   External
    Review Draft.  April 1979.

U.S. EPA (U.S. Environmental Protection Agency).   1980m.   Ambient water quality
    criteria for cyanides.  U.S.  EPA Office of Water Regulations and Standards.
    Criteria and Standards Division.    Report No.  EPA 440/5-80-037.   October
    1980.

U.S. EPA (Environmental  Protection Agency).  1980n.   Problem oriented report:
    Health Assessment of Nickel.   Environmental Criteria  and Assessment Office,
    Office of Health and Environmental  Assessment,  Office of Research and
    Development, U.S. Environmental  Protection Agency,  Research  Triangle Park,
    NC.  Internal Review Draft,  December 1980.
Van Duuren, B.L., and B.M.  Goldschmidt.   1976.
    promoting agents in tobacco carcinogenesis.
    56:1237-1242.
Cocarcinogenesis
 J. Nat!.  Cancer
and tumor
Inst.
Venugopal,  B. and T.D.  Luckey.   1978.   Chemical  toxicity  of  metals  and
    metalloids.   In:  Metal  toxicity in  Mammals.   2.   Plenum  Press.   New York.

Wallcave,  L. , H.  Garcia,  R.  Feldman,  W.  Lijinsky,  and P.  Shubik.  1971.   Skin
    tumorgenesis  in mice  by  petroleum asphalts  and coal-tar  pitches  of known
    polynuclear aromatic  hydrocarbon  content.   Toxicol. Appl.  Pharmacol.
    18:41-52.

Wang,  I.Y.,  R.E.  Rasmussen,  N.L.  Petrakis,  and  A.C.  Wang.  1976.  Enzyme
    induction and the difference  in the  metabolite patterns  of benzo[a]pyrene
    produced  by various strains  in  mice.   In:   Carcinogenesis. Vol.  1:
    Polynuclear Aromatic  Hydrocarbons:   Chemistry, Metabolism, and
    Carcinogenesis.  Freudenthal, R.I.,  and P.W.  Jones, editors.  Raven Press,
    New York, pp. 77-89.
                                      175

-------
Wiebel, F.J., J.C. Leutz,  and H.V.  Gelboin.   1973.   Arylhydrocarbon
    benzo[a]pyrene hydroxylase:   Inducible  in extrahepatic  tissues of mouse
    strains not inductible in liver.   Arch.  Biochem.  Biophys.  154:292-294.

Wiebel, F.J., J.C. Leutz,  and H.V.  Gelboin.   1975.   Arylhydrocarbon
    benzo[a]pyrene hydroxylase:   A  mixed-function  oxygenase in mouse skin.
    J. Invest. Dermatol.  64(3):184-189.

Workshop on Diesel Engine Exhaust.   1981.   U.S.  Environmental  Protection
    Agency, Office of Research and  Development,  Research Triangle Park, NC.
    February.

World Health Organization.  1979.  Environmental  Health Criteria.  10.  Carbon
    disulfide.  Geneva.

Yang, S.K., P.P. Roller,  and H.V. Gelboin.   1978.   Benzo[a]pyrene metabolism:
    Mechanism in the formation of epoxides,  phenols, dihydrodiols, and  the 7,8-
    diol, 9,10-epoxides.   In:  Carcinogenesis, Vol.  3:   Polynuclear  ARomatic
    Hydrocarbons:  Chemistry, Metabolism,  and Carcinogenesis.   Freudenthal,
    R.I., and P.W. Jones, editors.   Raven Press,  New York,  pp. 285-301.

Zampaglione, N.C., and G.J. Mannering.  1973.  Properties of benzpyrene
    hydroxylase in the liver, intestinal  mucosa and adrenal of untreated  and
    3-methylcholanthrene treated rats.  J.  Pharmacol. Exp.  Ther.
    185(3):676-685.
                                       176

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