&EPA
             United States
             Environmental Protection
             Agency '
             Office of Health and
             Environmental Assessment
             Washington DC 20460
EPA-600/6-82-003F
February 1984
Pinal Report
             Research and Development
Carcinogen              Final
Assessment of          Report
Coke Oven Emissions

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                                   EPA-600/6-82-003F
                                   February 1984
                                   Final Report
Carcinogen Assessment
                of
  Coke Oven Emissions

         Final Report
       Carcinogen Assessment Group
   Reproductive Effects Assessment Group
Office of Health and Environmental Assessment
    Office of Research and Development
    U.S. Environmental Protection Agency
        Washington, D.C. 20460

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                                  DISCLAIMER
    This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication.  Mention of trade names
or commercial products does not constitute endorsement or recommendation for
use.
                                     -ii

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                                    CONTENTS
Preface. .  ...... ............. .-••< •  .  -.  •  ...  •  .  •  ซv
Authors and Reviewers. ... .....  .  .  . .  * .;.......  .  .  .  .vi
  I.  Summary and Conclusions ..............  .... ^  ...  .1
         Summary ...... . ......... .  .....  ....... 1
         Conclusions .... .......... ......  ....... 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 Ceil Transformation  . .  ........ .....  27
         Studies Evaluating Sol vent-Extractable Organics of Coke Oven
           Door Emissions. .  . .....................  27
         Studies Evaluating the Complex Material from the Coke Oven
           Collecting Main ......  .  .......  .... .....  31
         Studies Evaluating Sol vent-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  ............................  51
         Cell Transformation  . .  ....................  52

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  V.  Toxicity	.  .	.54

         Acute  Toxicity of Coal Tar.  ;  . .	 54

         Subchronic and Chronic Toxicity of Coal Tar Aerosols. ..... 54


 VI.  Carcinogenicity	64

         Epidemiologic Studies 	 .64

         Animal Studies	116

         Carcinogenicity of Coke Oven Emission Components	143


VII.  Quantitative Estimation.	 .147

         Introduction. .....	 	 . . .147

         Estimation of the Unit Risk - Considerations. ... . .  . . . .149

         Data Base Available for the Estimation of Unit Risk ..... .157

         Age-Specific Esposure-Induced Respiratory Cancer Death
           Rate Models .	177

         Estimation of Lifetime Cancer Risk Due to a Constant
           Lifetime Exposure ..............;	186

         Composite Unit Risk Estimate		190

         Factors That Have the Potential for Biasing the
           Calculated Estimated Risks	191

         Summary	193


VIII.  References	196
                                      TV

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                                   PREFACE

    The Carcinogen Assessment of Coke Oven Emissions was prepared to serve as
a source document for U.S. Environmental  Protection Agency (EPA) use.  This
document was developed primarily for use  by the Office of Air Quality Planning
and Standards, to support decision-making regarding possible regulation of
coke oven emissions as a hazardous air pollutant.
    In the development of the assessment  document, the scientific literature
has been inventoried, key studies have been evaluated, and the summary and
conclusions have been prepared so that the carcinogenicity and related
characteristics of coke oven emmissions are qualitatively identified.
Measures of dose-response relationships relevant to ambient exposures are also
discussed so that the adverse health responses are placed in perspective with
observed environmental levels.

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                             AUTHORS AND REVIEWERS
     The Carcinogen Assessment Grpup,  Office of Health,and  Environmental
 Assessment,  was responsible for preparing this document.   Participating
 members are  as  follows (principal  authors are  designated by  asterisks):


     Roy E. Albert, M.n.  (Chairman)
     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.
     Charalingayya  B. Hiremath,  Ph.D.
     Robert McGaughy, Ph.D.                                        .
     Oharm V. Singh,  D.V.M., Ph.D.
     Nancy A. Tanchel,  B.A.
    *Todd W. Thorslund, Sc.D.


     The  Reproductive Effects  Assessment Group, Office of Health and
 Environmental Assessment was  responsible  for preparing the section on
 mutagenicity.   Participating  members are  as follows (principal authors are
 designated by asterisks):
    John R. Fowle III, Ph.D,
    Ernest Jackson, Ph.D.
    K.S. Lavappa, Ph.D.
    Sheila Rosenthal, Ph.D.
    Carol Sakai, Ph.D.
   *Vicki Vaughan-Oellarco,
    Peter E. Voytek, Ph.D.
Ph.D.
    The Carcinogen Assessment Group (CAG) also acknowledges the contributions
of the following in preparation of this document:
    Dr. Robert Bruce
    Environmental Criteria and
      Assessment Office,
    Research Triangle Park, North Carolina

    Mr. Joseph Santodopato
    Syracuse Research Corporation
    Syracuse, New York

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     The  following  individuals  provided  peer  review of this draft or earlier
 drafts of this  document:

 U.S.  Environmental  Protection  Agency                     •

 Dr.  Robert  Bruce                                   .  ,
 Health Scientist,  Environmental Criteria
   and Assessment Office
 Office of Research  and Development
 Research Triangle  Park, North  Carolina

 Dr.  Roger Cortesi                                        •
 Acting Director, Office of Health Research
 Office of Research  and Development
 Washington, D.C.

 Dr.  Seymour Holtzmann
 Biologist,  Office of Environmental
   Processes and Effects Research
 Office of Research  and Development
 Washington, D.C.                                       ;

 Dr. Joellen Lewtas
 Chief, Genetic Bioassay Branch
 Health Effects Research Laboratory
 Office of Research  and Development         -     .
 Research Triangle Park, North Carolina

 Dr. Debdas Mukerjee
 Oncologist, Environmental Criteria
   and Assessment Office
 Office of Research  and Development
 Cincinnati, Ohio

 Dr. Stephen Nesnow
 Chief, Carcinogenesis and
   Metabolism Branch
 Health Effects Research Laboratory
 Office of Research  and Development
 Research Triangle Park, North Carolina

 Mr. Joseph Padgett
 Director, Strategies and
   Air Standards Division
 Office of Air, Noise, and Radiation
 Durham,  North Carolina

 Mr. Gerald Rausa
 Health Research Coordinator
 Office of Health Research
 Office of Research and Development
Washington,  D.C.
                                     vTi

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Dr. non Tang
Staff Engineer
Office of Environmental  Engineering
  and Technology
Office of Research and Development
Washington, n.C.

Dr. John Todhunter
Assistant Administrator
Office of Pesticides and
  Toxic Substances
Washington, n.C.

Other Agencies

Dr. Charlie Rrown
Biology Branch
National Cancer Institute
Bethesda, Maryland

Dr. Michael Rowe
Biomedical and Environmental
  Assessment Division
Brookhaven National Laboratory
Upton, New York

Dr. Joyce Salg
Epidemiologist
Division of Surveillance,
Hazard Evaluations, and Field Studies
National Institute for Occupational
  Safety and Health
Cincinnati, Ohio

Consultants Outside of Government

Dr. Bernard Altschuller
Institute of Environmental  Medicine
New York University Medical Center
Tuxedo, New York

Dr. Melvin Benarde
Professor of Epidemiology  and
   Community Medicine
Hahnemann Medical College  and
   Hospital
Philadelphia,  Pennsylvania

Dr. Dietrich Hoffman
Naylor  Dana Institute For
   Disease  Prevention
American  Health Foundation
Valhalla,  New  York
                                      viii

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Dr. Carol Redmond
Department of Biostatisties
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, Pennsylvania
EPA_Science_Advi sory_Board

     The substance of this document was independently peer-reviewed in public

sessions of the Environmental Health Committee of EPA's Science Advisory

Board.



     The Carcinogen Assessment Group is appreciative of the public comments

received, especially those of Dr.  Steven Lamm,  Consultants  in  Epidemiology

and Occupational Health, whose comments were helpful  in revising the  document.
                                      IX

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                          I.  SUMMARY AND CONCLUSIONS
 SUMMARY
 Qual1tati ve As ses sment
     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.,
 beta-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  epidemiologic 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 in 1975 was  6.94 among Allegheny County,  Pennsylvania coke
 oven workers who had been employed 5 or more years through 1953 and worked
 full-time topside at the coke ovens.  By comparison, side oven workers
employed more than 5 years and followed through 1975 had a relative 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 at time of entry to the study

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 (1951-1955), the  relative  risk in 1975 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 among white coke oven workers in Allegheny County (relative risk in
 1975 of 8.50 for those employed 5 years or more through 1953 and 5.42 for
 those ever employed through 1953).  Prostate cancer mortality was found to be
 significantly (P < 0.05) elevated for the nonwhite non-Allegheny County coke
 oven workers ever employed or employed for 5 years or more (relative risks of
 2.45 and 3.69 respectively in 1975) and for all  workers at the coke ovens in
 Allegheny County ever employed through 1953 (relative risk of 1.67 in 1975).
    Sakabe et al. (1975) observed a significant (P < 0.05) excess of lung
 cancer deaths (lung cancer mortality ratio 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, particularly when the
 lung cancer mortality ratio is one that could be explained by differences in
 smoking habits.
    British studies of coke oven workers do not show the magnitude of risk
 found in the American studies or the Sakabe et al. study.   Davies (1977, 1978)
 found no excess mortality for coke oven workers when compared to the general
population.  However, a short observation period and a relatively small  sample
 size (number = 610) are shortcomings of this study.  Reid and Buck (1956) did
not find an excess of respiratory cancer among British coke oven workers.
They did find an excess in mortality from cancer,  other than respiratory

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 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,  however.   Coll ings  (1978)  found an increase in  lung cancer
 deaths among  British coke  plant  workers,  but the increase  was not
 statistically significant.   The  period of observation was  short  (only 9
 years),  and Coll ings included nonoven  as  well  as coke oven workers  in his  coke
 oven  plant  cohort.   Comparisons  among  occupational subgroups  (non-oven,
 part-oven,  and  coke oven)  failed to show  a statistically significant
 difference, but the sample  sizes of the "non-oven" and  "part-oven"  groups  were
 relatively  small (392  and  742, respectively).
     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 and  as a promoter following initiation
 with benzo[a]pyrene  (Nesnow et a!. 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
participates 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 (Norton
et al. 1963, Tye and Stemmer.1967, Kinkead 1973,  MacEwen and Vernot  1976).
Numerous  other 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.
Quant1tatlye Assessment
    A number of approaches are used to estimate the human lifetime respiratory
cancer death rate due to a continuous exposure of 1 ug/m3 of the benzene
soluble organics (BSO) extracted from the particulate phase of CTPV from coke
ovens emissions.
    Using a Weibull-type model it is estimated that the risk due to a 1
ug/m3 unit exposure ranges from 1.30 x 10~8 for the 95% lower-bound zero
lag-time assumption to 1.05 x 10~3 for the 95% upper-bound 15-year lag-time
assumption.  Using a multistage-type model, the maximum likelihood estimates
for the risk due to unit exposure range from 1.76 x 10~6 for the zero
lag-time case to 6.29 x 10"4 for the 15-year lag-time case.
    Since it is not known whether either of these models reflects the true
dose-response relationship at low doses, a range of estimates from zero to an
upper bound is a more appropriate indicator of potential risk.  To obtain this
upper bound, a linearized modification of the multistage model is used, giving
a unit risk value of 1.26 x 1Q-3 as the highest potency amongst the four
lag-time data sets.  The lower bound of the range approaches zero.
    A composite unit risk estimate is obtained from the multistage 95%
upper-bound estimates for each of four lag-times by taking their geometric
mean.  This results in a composite estimate of 6.17 x 10-4, which is

                                      4

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 regarded as the most plausible upper-bound estimate.
     It should be noted that the ranges of these  results do not reflect the
 total uncertainty connected with these estimates.  Other factors that could
 change the results, such as cigarette smoking rates and sex-race sensitivity
 differences, were not accounted for due to lack  of sufficient information.
CONCLUSIONS
    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 as a
result of exposure to coke oven emissions.  These risks may possibly have been
enhanced by smoking but are not believed to have been confounded by smoking.
Both an 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.  In
multiple experiments, mice exposed to coal tar aerosol developed lung tumors.
Sample extracts from a coke oven topside sample and a coke oven main initiated
tumor formation in initiation-promotion studies in mice.  Coke oven door
emissions were found to be mutagenic in bacteria.  Numerous constituents of
coke oven emissions are known or suspected carcinogens.
    The preceding findings constitute sufficient evidence for carcinogenicity
in humans, and sufficient evidence for carcinogenicity in experimental  animals
if the International  Agency for Research on Cancer (IARC) criteria were used
for the classification of carcinogens.  Therefore, coke oven emissions  would
be classified in IARC category 1, meaning that this mixture is carcinogenic to
humans.
    Using a linearized multistage model  and averaging the upper-bound
estimates from multiple data sets, the most plausible upper-bound unit  risk
estimate is approximately 6.2 x 10"4.  This value is the estimated
individual  lifetime risk associated with a continuous exposure of 1
of coke oven emissions in ambient air.

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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  larry  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
1046ฐC  (1900ฐF) to 1100ฐC  (2000ฐF) 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
700ฐC (1292ฐF) 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 700ฐC (1292ฐF).   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 760ฐ to 870ฐC and
is shock cooled by spraying recycled  "flushing liquor"  into the collection

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main.  This spray cools the gas to 80ฐ to 100ฐC, 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
                                                                    ซ
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 60ฐC is taken to final coolers or
condensers, where it is typically cooled with water to approximately 24ฐC.
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.
                                       8

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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
              Large Coke Particulates
              Coke Oven Gas
              Tar
              Ammonium Sulfate
              Ammonium Liquor
              Light Oil
 545-635 kg
  49-90 kg
 285-345 m3
27.5-34 1
   7-9 kg
   5-135 1
   3-12.5 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.
    An OSHA standard for coke ovens emissions was issued in 1978 (29 CFR
1910.1029).  This standard is a comprehensive standard which includes
requirements for exposure monitoring; medical  surveillance; use of respirators,
protective clothing, and equipment; training and education; hygiene facilities
and practices;  etc.  The permissible exposure limit (PEL) as defined by the
standard is an  8-hour time-weighted average of 150 ug/m3 of the benzene
soluble fraction of total  particulate matter.

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       TABLE II-l.
PARTIAL LIST OF CONSTITUENTS OF COKE OVEN EMISSIONS
            (U.S. EPA I978a)
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
Dihydroanthracene
Dihydrobenzo[a]fluorene
Di hydrobenzo[b]fluorene
Dihydrobenzo[c]fluorene
Dihydrobenz[a]anthracene
Dihydrochrysene
Di hydrof1uoranthene
Dihydrofluorene
DihydromethylbenzCa]anthracene
DihydromethylbenzoCk and b]fluoranthenes
DihydromethylbenzoCa and e]pyrenes
Dihydromethylchrysene
                           Dihydromethyltriphenylene
                           Dihydrophehanthrene
                           Dihydropyrene
                           Dihydrotriphenylene
                           Dimethylbenzo[b]f1uoranthene
                           Dimethylbenzo[k]fluoranthene
                           Dimethylbenzo[a]pyrene
                           Dimethylchrysene
                           Dimethyltriphenylene
                           Ethyl anthracene
                           Ethylphenanthrene
                           Fluoranthene
                           Fluorene
                           Indeno[l,2,3-cd]pyrene
                           Methyl anthracene
                           Methylbenzo[a]anthracene
                           Methylbenzo[a]pyrene
                           Methylbenzo[ghi]perylene
                           Methylchrysene
                           Methylfluoranthene
                           Methy!fluorene
                           Methylphenanthrene
                           Methylpyrene
                           Methyltriphenylene
                           Octahydroanthracene
                           Octahydrofluoranthene
                           Octahydrophenanthrene
                           Octahydropyrene
                           Perylene
                           Phenanthrene
                           Indenb[l,2,3~cd]pyrene
                           Pyrene
                           Tri phenylene
POLYNUCLEAR AZA-HETEROCYCLIC COMPOUNDS
Acridine
Benz[c]acridine
Dibenz[a,h]acridine
Dibenz[a,j]acridine
AROMATIC AMINES
a-Naphthylamine
3-Naphthyl ami ne
TRACE ELEMENTS
Arsenic
Beryllium
Cadmi urn
Chromium
Cobalt
Iron
Lead
Nickel
Sel eni urn
                                              (continued  on  the  following page)
                                        10

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                            TABLE II-l.  (continued)
OTHER AROMATIC COMPOUNDS

Benzene
Phenol
To!uene
Xylene
.OTHER GASES

Ammonia
Carbon disulfide
Carbon monoxide
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 lead 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
                                      12

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 understanding  of the  general mechanisms  involved in POM biotransformation.  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
                                      13

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                      (ENDOPLASMIC
                        RETICULUM)
   BaP-O-SG
 (DETOXIFICATION
   PRODUCTS)
 GLUTATHIONE
ซ	:	.	
 TRANSFERASE
  (CYTOSOL)
                    CYTOCHROME P-450
                    MIXED-FUNCTION OXIDASE (MFO)
                                              MFO
                               BaP OXIDES
                                     EPOXIDE
                                     HYDRASE
                                     (ENDOPLASMIC
                                     RETICULUM)
                                                        BaP PHENOLS
                                              MFO
                                                        BaP GUI NONES
                       MFO
             BaP DIOL EPOXIDES
            (PROPOSED ULTIMATE
              CARCINOGENS)
                              BaP DIHYDRODIOLS (PROPOSED PROXIMATE CARCINOGENS)
                            UDP-GLUCURONOSYL TRANSFERASE
                                (ENDOPLASMIC RETICULUM)
                              H2O-SOLUBLE CONJUGATES
                              (DETOXIFICATION PRODUCTS)
Figure  III-l.  Enzymatic pathways involved  in the activation and
            detoxification of  B[a]P (U.S.  EPA 1979).
                                     14

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discussions are based upon the available experimental evidence regarding
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 diagram shows three groups of
positional  isomers, three dihydrodiols,  three quinones, and several  phenols.
                                      15

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                       BENZO(a)PYRENE

                        /I
                        6-OH-Me
6-PHENOXY
  RADICAL
                                       7 8-epox
               7, 8-diol
                         [7,8,9,10-tetroj]
                          7-OH
                    I
           CONJUGATES
BOUND MACROMOLECULES
      DNA
      RNA
      PROTEIN
  Figure  111-2.  Metabolites of benzo[a]pyrene  (U.S.  EPA  1979)
                              16

-------
 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
anj,mals 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

-------
nutritional status, and exposure to enzyme-inducing chemicals.   Limited
evidence is also available indicating that multiple forms of epox-ide 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
                                                   f
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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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 glucuronic acid or by  further  metabolism to
                                      20

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tetrahydrotetrols.  Glutathlone 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 3-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
                                NOH
                   -N =
                amine
hydroxylamine
                                              nitroso
-N02
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 a-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
 metallothionein 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 metal!oprotein (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.S. 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
   Absorbent    Filter
                   Length of Sampling Segments
   Al
   A3

   A5

   A6
A1F
ASF

ASF
(hr)
 1 (represents the first hour of the coking  cycle)
 2 (represents the beginning of the third hour  up
   to the fifth hour)
 5 (represents the beginning of the ninth hour
   through the thirteenth hour)
— 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 in TA 98 were observed without S-9 mix for  the filter
extract samples A1F, ASF, 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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29

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 greatly  enhanced the mutagenic  response  for all filter extract samples in
 strains  TA 98, TA  100, TA  1538, and TA 1537.  The filter extracts were not as
 active in TA  100 as they were in the other tester strains.  These responses
 appeared as concentration-related increases in revertant colonies (see Figure
 IV-1  B).  "Toxic effects"  were  reported  for sample A5F at 10 ul.  A1F, ASF,
 and ASF 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 ug/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 cerevlsiae 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 organics of air participates 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 organics 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 ..
    600 _
   0)
   R
   3400
   '300 __
    200 __
    100 --
                                                              TA. 98
                                                             TA 1538
                                                             TA. 100
                                                             TA. 1537

                                                             TA. 1535
                                                             TA 1536
                 200
400       600      800

        ug per plate
1000
Figure IV-2.  Mutagenic 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 Salmonel1 a/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 MUTA6ENIC ACTIVITY IN SALMONELLA TYPHIMURIUM
                   OF ORGAN ICS EXTRACTED FROM AIR PARTICULARS  UOLLECTtU
                        IN INDUSTRIAL AND RESIDENTIAL AREAS OF  JAPAN*
Sample Number
Revertants per n)3 air
Industrial Areast
123 (coke mill)
160
161
162
163
164
         445.0
         288.0
          94.0
          22.2
         138.0
         103.0
Residential Areasง
 86
152
 21
150
 64
126
          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.
     งSamples 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 mutagenic
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
mutagenic 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 mutagenic activity (i.e.,
revertants/m3) determined from the highest concentration tested should be
very similar to the mutagenic 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 mutagenic 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 mutagenic 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 mutagenic than
residential  samples (but not for the other industrial  sources) when the data
were expressed as revertants/ug.
                                      39

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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
m3/min 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 jni.
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 v arrant colonies were only
observed at high cell killings.  For example, at 200 ug/ml (82% cell killing)

   ^Percentage of relative total growth =  (relative suspension growth/relative
cloning efficiency) x 100.
                                      42

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a threefold Increase In 6-thioguanlne (6T6)  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^ 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 Saccharomyces 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  represent!ve 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
parti culates.
     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 Moller and Dybing (1980),  urine  concentrates from
coke plant workers were evaluated for their mutagenic  effects in the
Salmonel1 a/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.)
                  ซ
 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 g-glucuronidase (which  hydrolyzes  possible
                                      47

-------
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 Holler 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 OR6ANICS
IDENTIFIED IN
Chemical S-9
Acenapthylene
Acridine
Aniline
Anthracene
Benz[a]anthracene
Benzo[a]pyrene
Benzo[b]f1uorene
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
Responseง
+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 orcoke oven emissions extracted from reports by Bjorseth
et al. (1978) and U.S. EPA (1977b).

    tA, Aroclor-induced; PB, phenobarbital-induced; N.A., not available.

    งData 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
Fl uorene
Indole
Isoquinoline
Naphthalene
Naphthylamine
Peryl ene
Phenanthrene
Pyrene
Pyridine
Quinoline
Triphenylene
S-9 Activationt
A
A, PB
A, PB
A, PB
A, PB
A
A
A, PB
N.A.
A, PB
A
A
Reported
Responseง
+b,c
_a,b
_b
_b,c
_a,b,c
+a,c
+b
_a,b,+c
+c
+b
+b,c
+b,c
งData 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

-------
or negative in the Salmonel1 a/microsome assay.  [A positive response in this
test appears to he 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  -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 jn 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
    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

-------
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 th.e
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 particulates (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

-------
 (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 V-3 and V-4).  However, in
 contrast to treated mice, decreased body weight gain rather than marked  loss
 occurred during treatment, and a dose-response in  reduced body weight  gain is
 clearer for weanling rats.  Even the lowest exposure concentration,  0.2
 ug/m3, produced some adverse effects on body weight  gain.   Following the
 termination of exposure, the inhibitory effect of  coal  tar aerosol  on  growth
was still evident for at least 7 months in most species.
    Kinkead conducted a subsequent coal  tar experiment in  which  the  solid
                                      55

-------
              40
              35
          S


          I
          1-

          o
          o
          CO
          IU


          3
          IT
          IU
              30
              25
              20
      0.0 mg/m3

      0.2 mg/m3

      2.0 mg/m3

      10 mg/m3

O	 20 mg/m3
                    •EXPOSURE-
                                         -POST EXPOSURE-
                           23456789


                                   DURATION (months)
Figure V-l.   Growth of male CAF-1  mice exposed to coal  tar aerosol

               (Kinkead 1973)
                                     56

-------
            O
            to

            I
            ง
            ui
            C3
            <
            tr.
            ui
                 45
                 40
35
30
                 25
      0.0 mg/m3
      0.2 mg/m3
      2.0 mg/m3
•	 10 mg/m3
O     20 mg/m3
                     -EXPOSURE-
                                       -POST EXPOSURE-
                            234567

                                  DURATION (months)
                                   8   9   10
Figure V-2.  Growth of male ICR mice exposed to coal  tar aerosol
              (Kinkead 1973)
                                    57

-------

                   Q
                   O
                   m
                   ill
                   0
                   <
                   DC
                   til
650


600

550

500

450

400

350

300

250

200

150

100

 50
0.0 mg/m3
0.2 mg/m3
2.0 mg/m3
10 mg/m3
20 mg/m3
                           -— EXPOSURE-
                                              -POST EXPOSURE-
                          01   23456789   10

                                           DURATION (months)
Figure V-3.   Growth  of male  weanling rats  exposed  to coal  tar aerosol
               (Kinkead 1973)
                                      58

-------
                380 r
                340
                300
           ~   260
           I-
            uu
            Q
            O
            CD
            UJ
            s
            IT
            UJ
                220
180
140
                100
                 60 '
0.0 mg/m3
0.2 mg/m3
2.0 mg/m3
10 mg/m3
20 mg/m3
                                       4567

                                       DURATION (months)
                                                                    10
Figure  V-4.   Growth of  female weanling  rats exposed to coal  tar aerosol
               (Kinkead 1973)
                                       59

-------
particles and light oil  fractions were retained in the experimental  aerosol.
Sprague-Dawley rats, New Zealand white rabbits, JAX mice,  and Syrian golden
hamsters (numbers not specified) were exposed continuously for 90  days  to  the
coal tar aerosol at a concentration of 10 mg/m3.  In addition, 150 CF-1 mice
were exposed to the aerosol and serially sacrificed for histopathologic
analysis.  Among exposed rats and hamsters,  McDonnell  and  Specht  (1973)
described three significant lesions occurring at the termination of  exposure.
These were:  1) phagocytized coal tar pigment in alveolar  macrophages and  in
the peribronchial lymphoid tissue; 2) hepatic and renal hemosiderosis which
disappeared by 100 days post-exposure; and 3) mild central  lobular necrosis in
the liver.  Among mice sacrificed 99 days post-exposure, moderate  pigmentation
of alveolar macrophages was observed in 14 of 15 CF-1 mice, but in only 1  of
13 exposed JAX mice.
    In a follow-up study, MacEwen and coworkers (1976) prepared a  composite
coal tar mixture collected from multiple coking ovens around the greater
Pittsburgh area.  Coal tar samples were blended together with a 20%  by  volume
amount of the BTX (benzene, toluene, xylene) fraction of coke oven distillate.
This material was believed to be more representative of that inhaled by
workers on top of coke ovens.  Female (75) ICR-CF-1 mice,  female  (50)
CAF-1-JAX mice, male (40) and female (40) weanling Sprague-Dawley  rats, New
Zealand white rabbits (18), and male (5) and female (9) Macaca mullata  monkeys
were exposed to a coal tar aerosol at 10 mg/m3, 6 hours daily, 5 days/week,
for 18 months.  Animals were held for an additional 6-month observation period
following termination of exposure.  A significant inhibition of body growth
rate was observed for both male and female rats after 4 months and for  rabbits
by the end of the first month (Figures V-5 and V-6).  Monkeys showed no
significant inhibition of growth rate from exposure to the coal tar  aerosol
                                      60

-------
 too
                             to  M a  a 14  o ซ• IT
Figure V-5.
The effect of repeated exposure to 10 mg/m3 coal tar  aerosol  on
growth of rats.
(MacEwen et al . 1976)
                        61

-------
          i.O
          4.A
          4.O
          "
          1.0
          X.9
          t.O
                                                         J  '
Figure V-6.
The effect of repeated  exposure to 10 mg/ra3 coal tar aerosol
on growth of rabbits  and  monkeys.
(MacEwen et al. 1976)
                                    62

-------
(Figure V-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
EPIDEMIOLOGIC 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 mortality from cancer at all sites; cancer of the lung,  trachea, and
bronchus; cancer of the kidney; and cancer of the prostate.  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 Ceilings (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 which may have prevented the detection of any cancer risks.

Ame ri can Studi e s
    In 1962 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).
                                        64

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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,
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.
                                       69

-------
 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 steel workers population to the number at risk in the work
 area.  A Standard Mortality Ratio (SMR)* was calculated for each area.  The
 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  steel workers 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).   SMRs for other causes
     *CMD   Observed Deaths   iriri
      SMR = Expected DeathT x 10ฐ
                                       70

-------
 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
 steel worker 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.
                                       71

-------
    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 VI-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
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 VI-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
                                       72

-------
TABLE VI-2.  DISTRIBUTION OF COKE PLANT WORKERS EMPLOYED IN ALLEGHENY COUNTY,
                  PENNSYLVANIA IN 1953 BY WORK AREA AND RACE
                          (adapted from Lloyd 1971)
             Coke Plant
    Coke Oven
Number     Per Cent
     Nonoven
Number      Per Cent

Total
White
Nonwhite

3,530
2,369
1,161
Employed in 1953 or
2,048
993
1,055
Prior Years
58.0
41.9
90.9

1,482
1,376
106

42.0
58.1
9.1
                                     73

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    TABLE VI-4.  NUMBER EMPLOYED, OBSERVED AND EXPECTED LUNG CANCER DEATHS,
AND STANDARDIZED MORTALITY RATIOS (SMRs) OF MEN EMPLOYED IN SELECTED COKE OVEN
SUBDIVISIONS IN ALLEGHENY COUNTY, PENNSYLVANIA IN 1953 AND PRIOR YEARS BY RACE
                           (adapted from Lloyd 1971)

Total Coke Oven
White
Nonwhite
Side Oven
White
Nonwhite
Partial Topside
White
Nonwhite
Full Topside
White
Nonwhite
Number
Employed
2048
993
1055
1431
606
825
315
307
8
302
80
222
Observed
Lung Cancer,
Deaths
31
8
23
10
5
5
2
2
0
19
1
18
Expected
Lung Cancer
Deaths
12.3
4.7
7.6
8.0
2.7
5.4
1.7
1.6
0.1
2.6
0.5
2.2
SMR
252*
170
303*
125
185
93
	 -J-
___+
	 -j-
731*
	 	 •ป•
818*
    *Significant at P < 0.01.

    tLess than five deaths in  both observed and expected;  SMR and statistical
significance not calculated.
                                       75

-------
 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
 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 workers employed only at the same side of the oven or with less
than 5 years employment at fulltime topside jobs.
                                       76

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    TABLE VI-5.  NUMBER EMPLOYED, OBSERVED AND EXPECTED LUNG CANCER DEATHS,
    AND STANDARDIZED MORTALITY RATIOS (SMRs) OF MEN EMPLOYED AT COKE OVENS
      IN ALLEGHENY COUNTY, PENNSYLVANIA IN 1953 AND PRIOR YEARS BY LENGTH
                     OF EMPLOYMENT (AS OF JANUARY 'l, 1953)
                           (adapted from Lloyd 1971)



Less Than 5 Years
White
Nonwhite
5 or More Years
White
Nonwhite

Number
Employed
1144
593
551
904
400
504
Observed
Lung Cancer
Deaths
4
3
1
27
5
22
Expected
Lung Cancer
Deaths
4.7
2.2
2.6
7.6
2.6
5.1


SMR
— t
— t
— t
355*
192
431*
    tLess than five deaths in both observed and expected;  SMR and  statistical
significance not calculated.
                                      77

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  TABLE VI-6.   NUMBER  EMPLOYED,  OBSERVED  AND  EXPECTED  LUNG CANCER DEATHS, AND
       STANDARDIZED  MORTALITY  RATIOS  (SMRs) OF 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)



Side Oven Only
White
Nonwhite

Number
Employed
496
171
325
Observed
Lung Cancer
Deaths
6
2
4
Expected
Lung Cancer
Deaths
4.1
1.1
3.0


SMR
146
— t
— t
Side and Topside
(less than 5 years
full-time topside)
White
Nonwhite
Full-time Topside
White
Nonwhite


276
202
74
132
27
105


6 •
2
4
15
1
14


2.1
1.3
0.8
1.5
0.2
1.3


286*
— t
	 	 -j-
1000*
___ +
1077*
    *Significant at P < 0.01.

    tLess than five deaths in both observed and expected;  SMR and statistical
significance not calculated.
                                       78

-------
 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.  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.
    It should  also be noted that any confounding due to smoking would tend to be
 reduced  by the use of an internal  comparison group such as was done in this
 study.   Smoking habits are known to vary by the nature of the occupation.   A
 comparison of coke oven workers to other steel workers, such as was done in this
 study, would tend to minimize differences that  might be present were another
 comparison group, such as the general  population,  to be used.  Naturally,
 however, such a comparison cannot  eliminate individual  differences in smoking
 habits that might be present between the coke oven workers and the other
 steelworkers.
    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
                                        79

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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
                                       80

-------
 by differential  cigarette smoking experience.   Again,  a  synergistic effect  of
 coke oven  emissions  and smoking cannot  be ruled out.

 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 and who were of
 the  same race and of similar date of  initial employment as the coke oven 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 seco'nd 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.
                                       81

-------
     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

 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
                                       82

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 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
 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) 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.
    Hhen 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
 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
                                       84

-------
 for "other  malignant  neoplasms," which was significantly  (P < 0.01) less than
 expected  among  workers  having worked less than 5 years.
     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 (BSO)  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 BSO 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 >^ 700 mg/m3-months.
Age-adjusted data for  the total  number  of nonwhite workers showed  a clear
                                       85

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-------
 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
 workers  (Table VI-10).   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."  A
 further discussion of the difference in the white/nonwhite dose-response is
 contained  in the Quantitative Estimation Section  of  this document.
    Mazumdar et al.  found that lung cancer mortality was less  than  expected for
workers exposed to _< 200 mg/m3-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.
                                      87

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                                            88

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 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
 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-11.
 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-12).
                                        89

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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  risks 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-13).
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-13.  In addition to the tumor sites
listed in Table VI-13, 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 respir-
atory  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 of  mortality from all cancers and  from cancer of the
lung,  trachea, and  bronchus; kidney;  and  prostate  is reported  in,Table VI-14.
                                       92

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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-15



 and  VI-16).  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.
                                       95

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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
third group was composed of laborers whose duties and contacts with the
                                       98

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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-17.
    There was a significant difference between observed and expected mortality
for all other cancer combined (minus respiratory cancer) for oven 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 (P <0.05).  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
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
    *This division was proportionally distributed according to the work
histories of the 10% random sample (800 workers).
                                       99

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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 recently exposed 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 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 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
                                      101

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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.

navies  (1977, 1978) —
    navies  (1977,  1978)  reported on the mortality experience from May  1954 until
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;  88 had  died during the follow-up period.  Male mortality  rates for
                                       102

-------
 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,  particularly given the small  sample size (Number =
 610), may not be 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.

 Ceilings  (1978)--
    Collings  (1978)  conducted  a follow-up study of 2,854  male coke workers
 employed  in 14 coke plants 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
                                      103

-------
coke plants.  For each person in the cohort, a questionnaire was submitted to
the respective coke plants 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 "non-ovens" 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,
non-ovens,  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.
                                       104

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      Expected mortality  for the CMF 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 the
coke plant worker rates are contrasted with rates in Great Britain (45.0
observed vs. 35.7 expected, P = 0.12).  If only the coke plant 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 plants  during data collections
                                      105

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(1973 to 1975), and who attended the works medical  center at  that  time.   This
represented only 41% of the workforce.   Based on this  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 plants 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
non-ovens, the comparative mortality figure computed for each occupational  group
for certain selected causes, including lung cancer, revealed no statistically
significant excesses.  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 he does not state whether these
excesses were  statistically significant nor does he provide any data to support
this statement.
    The  risk of  lung cancer as  well as the risk  of all malignant neoplasms
increased with increasing lengths of employment  for the  1471 coke oven workers.
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.  None of  these SMRs  or CMFs were statistically  significant, however.
The  findings  above,  the author  concludes, tend  to  support American studies that
 show an excessive  risk of lung  cancer  in  coke workers despite the fact  that none
of the findings  were statistically  significant.
     Several  comments should be made regarding the  lack of statistical
 significance.   First,  Col lings compared the  observed  lung cancer  mortality  in
 coke plant workers, which included not only  coke oven workers  (Number = 1615)
                                       106

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but "part-oven" workers (Number = 742) and "non-oven" workers (Number = 392)  a's
well, with the mortality expected based on national  lung cancer mortality rates.
In other words, persons not even exposed to coke oven emissions, the non-oven
workers, and persons only occasionally exposed, the  "part-oven" workers were
included in the study cohort.  The diluting effect caused by the inclusion of
persons not even exposed or seldom exposed may well  be responsible for the lack
of a statistically significant excess of lung cancer mortality.
    Second, it should be noted that the sample size  of the "nonoven" (Number  =
392) and "part-oven" groups (Number = 742) are too small for a meaningful lung
cancer mortality comparison by CMF across occupational subgroups (coke oven,
"part-oven" and "non-oven").
    Third, the analysis by length of employment does not consider a
"survivorship effect" in regard to the analysis by SMR and is misleading in
regard to the analysis by CMF.  A "survivorship effect" (Fox and Collier 1976)
means that workers who survive, for example, 10 years of employment, will have a
lower lung cancer SMR and a lower SMR for other diseases than workers who began
employment at the same time but had left the working population.  Thus the
relative risk for coke oven workers who had worked ten or more years (SMR = 127)
would likely have been even higher had a similar working population, such as
other steelworkers as was used in the Redmond et al. studies, been used to
calculate the relative risk.  The CMFs as presented  are misleading because while
they may not indicate that coke oven workers employed 10 years or more have a
significant excess of lung cancer mortality in regard to the entire group of
coke plant workers, one should understand that the difference between the CMF
for workers employed less than 5 years and the CMF for workers employed ten or
more years is significantly (P < 0.05) different.
    Fourth, the study by Collings followed workers for only 9 years.  Such a
                                      107

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follow-up period is usually not long enough to detect a  significant  excess  of
cancer mortality if the mortality is associated with the suspected etiologic
agent being studied.
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 peripd 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 1300ฐC for blast
furnace coke, 1000ฐC for casting coke, and 1200ฐC 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
    *Although 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.
                                      108

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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
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 5 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).  Among 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
                                      109

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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
workers from city gas companies.  The difference of observed to expected,
however, is of a magnitude that could be explained by differences in smoking
habits, and thus, conclusions from the study, because of the inadequate smoking
data, are somewhat limited.  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 100ฐC to 300ฐC 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.
                                      110

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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
                                     111

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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 prostate cancer
    *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.
                                     112

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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.
 The excess  found,  however,  is of a  magnitude that  could  be  explained by
 differences in  smoking habits.   Thus, because  smoking data  for the  study was
 inadequate, conclusions from the study  are somewhat limited.
      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.
    navies (1977, 1978) did not find any significant difference  between  the
observed and expected cancer mortality of the coke oven workers  at two coke
works in South  Wales.  Davies's study cohort  was relatively  small  (Number =
610), however,  and  he followed his cohort for only 11  years.
                                     113

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    Ceilings (1978) found an excess of lung cancer among the coke plant
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, Col lings followed his cohort for a relatively short period of
time (9 years).  Also, his coke plant study cohort included nonoven workers as,
well as coke oven workers which would have caused a diluting effect, possibly
resulting in the failure to detect a significant increase.  An internal
comparison done by Collings did not find a significant difference between coke
oven workers and the entire cohort of coke plant workers, but the sizes of the
non-oven and part-oven subgroups were not large enough to have permitted a
meaningful analysis.  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 also contribute to the lack of positive
findings in the three British studies on coke workers (Reid and Buck 1956,
navies 1977, and Collings 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 had some design
deficiencies and 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 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
                                     114

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of the lung, trachea, and bronchus; kidney; and prostate,  as well  as cancer at
all  sites combined.
                                     115

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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
                                     116

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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-18.   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-19.   Promoting activity was found  with
the coke oven main  sample and TPA  following  initiation  with  B[a]P
                                     117

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           TABLE VI-18.
SENCAR MOUSE SKIN TUMORIGENESIS
(Nesnow et al.  1981)
Dose
(ug/mouse)

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

100
100
500
500
1000
1000
2000
2000
10,000
10,000
Mice with
No. Mice ! Papillomas*
Surviving (%)

(M)
(F)
(M)
(F)
(M)
(F)
M
(F)
(M)
(F)

(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

38
39
39
39
39
39
40
40
38
37
BENZO[A]PYRENE -
8
5
45
31
73
57
100
75
95
97
TOPSIDE COKE OVEN
13
10
73
70
95
72
95
90
100
100
COKE OVEN MAIN -
50
31
90
82
87
90
78
100
100
100
Mice with
Papillomas Carcinomast
per mouse* (%)
TUMOR INITIATION
0.08
0.05
0.50
0.44
1.8
1.1
5.8
2.8
10.2
7.9
- TUMOR INITIATION
0.13
0.20
1.6
1.8
2.6
2.0
4.0
3.5
7.1
7.7
TUMOR INITIATION
0.63
0.38
3.7
2.2
3.3
3.1
3.1
5.3
8.9
8.1

5
0
5
5
20
23
25
20
30
25

0
8
5
15
15
3
13
10
13
20

10
25
54
54
53
48
48
45
55
65
Carcinomas
per Mouset

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

0.10
0.25
0.59
0.54
0.53
0.48
0.48
0.45
0.55
0.65
*Scored at 6 months.
tCumulative score after one year.
                                 118

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            TABLE VI-19.  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 CARCINOGENESIS
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.
                                 119

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(Table VI-20).  Spontaneous tumor formation in the control  groups  was  not
evident in the studies for complete carcinogenesis and  promoting activity
(Tables VI-19 and VI-20) 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-18).
    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-18 and VI-19 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
                                      120

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                 TABLE VI-20.   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)ง
100 (F)
500 (M)
500 (F)
1000 (M)
1000 (F)
2000 (M)
2000 (F)
4000 (M)^l
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
    tMice initiated with 50.5 ug benzo[a]pyrene (B[a]P) and subsequently
treated weekly with acetone.


    งMice initiated with 50.5 ug (B[a]P) and subsequently treated weekly with
coke oven main.


    UMice 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.
                                     121

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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-18 and VI-19 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-20,  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.
                                     122

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 Coal Tar
     Cardnogenicity studies on aerosols of coal  tar and coal  tar fractions  in
 laboratory animals were reported by Morton (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),  Morton  (1961), and Wai leave  et al.  (1971).  Morton (1961) and
 Wallcave et al. (1971)  tested  coal  tar samples from coking operations.

 Inhalation  Exposure Studies--
     Morton  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
                                     123

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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-21).
     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
    *Tne initial size of the untreated group was not reported.   At  the
termination of the experiment at 82 weeks,  the group consisted  of 30 mice.
                                     124

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TABLE VI-21.  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
1/33
1/26
0/36
(0%)
(3%)
(4%)
(0%)
Total
0/30
7/33
2/26
0/36
(0%)
(21%)
(8*)
(0%)
                          125

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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%
 benzoCa]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 oflmthracene and  polycyclic aromatic hydrocarbons  with
  three  linear aromatic rings with a free meso position.
                                       126

-------
 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 mg/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 of
 the 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-22.
     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
                                     127

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TABLE VI-22.  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.
                                     128

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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/m3 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-23.
     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
    *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.
                                     129

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         TABLE VI-23.  TUMOR RESPONSE IN MALE ICR-CF1 AND JAX-CAF1  MICE
                    FOLLOWING EXPOSURE TO COAL TAR AEROSOL
                   (adapted from McConnell and Specht 1973)
Dose (rng/rn^)
20.0
10.0
2.0
0.2
0.0
ICR-CF1*
10/36
3/8
2/25
0/2
0/62
(28%)t
(38%)ง
(8%)ง
(oซ)ง
(0%)t
JAX-CAF1*
10/27
0/12
0/47
0/47
0/74
(37%)t
(0%)ง
(0%)ง
(0%)ง
(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.

    งThis dose group began with 50 animals.
                                     130

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 aerosol,  although  the  majority  of  these  tumors  fall  in the  squamous  cell

 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-24.   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 40

 females), 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
     o
 mg/m-3 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-25).   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,
                                     131

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     TABLE VI-24.   LATENT PERIOD  OF  FIRST  TUMOR  INDUCTION  IN CTV-I EXPOSED
                                 ICR-CF1 MICE
                          (McConnell  and Specht  1973)
        Dose (mg/m3)
Time of Tumor Appearance (Days)
            20

            10

             2
            < 93

             128

             142
    TABLE VI-25.   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%)
    *The numerator is the number of animals with tumors;  the denominator  is
the number of animals exposed.

    tlncludes the 90-day exposure period.
                                         132

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 18  New Zealand albino rabbits, and 5 male and 9 female Macaca mulatta monkeys
 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,
                                     133

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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
1'esion 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/m3 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-26.  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.
                                     134

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                   TABLE VI-26.  COAL TAR TUMORIGENESIS  IN RATS
                              (MacEwen et al. 1976)
                                         Controls
                                     Males     Females
    Exposed
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
o
0
0
8
100
38

31
0
n
\j
3
n
\J
2
82
             -1     	•  ~ •  •ซ~-' f'*- i  ;jivv*t-' ป*ซa -J TU ซ   i IWWG V C I $  UC*_aUoC Ul
 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,  n,  in)  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  historically.
                                     135

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    Tumor findings are described in Table VI-27.   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 metas-
tasizing to the lymph nodes.
TABLE VI-27.   INCIDENCE OF SKIN TUMORS IN MICE TREATED WITH BLAST FURNACE TARS
                      (adapted from Bonser and Manch 1932)

Number Of
Animals
with Tumors/
Tar Sample
Scottish I
Scottish II
Scottish III
English Crude
Number of
7/60
10/60
8/60
8/60
Animals
(12%)
(17%)
(13%)
(13%)
Appearance of
First Tumor
(weeks)
16
16
16
21

Malignant
Tumors
0/60 (0%)
2/60 (3%)
1/60 (2%)
0/60 (0%)
 Ether Extract
 of English Crude
24/60    (40%)
12
9/60    (15%)
                                      136

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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 Californi.an), 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 VI-28.
    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
                                     137

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    TABLE VI-28.  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
   Skin
Carcinomas
   Skin
Papillomas
   Total
Control
Coal Tar
Petroleum
Paraffin


Roofing Tar
Oil
0/200
22/50
1/50
1/50
(0%)
(44%)
(2%)
(2%)
0/200
4/50
0/50
1/50
(0%)
(8%)
(0%)
(2%)
0/200
23/50
1/50
2/50
(0%)
(46%)
(2%)
(4%)
Petroleum Road Asphalt
  Venezuelan               0/50     (0%)
  Mississippian            1/50     (2%)
  Oklahoman                0/50     (0%)
  Californian              1/50     (2%)
                   0/50
                   1/50
                   1/50
                   0/50
       (0%)
       (2%)
       (2%)
       (0%)
0/50
2/50
1/50
1/50
(0%)
(4%)
(2%)
(2%)
                                      138

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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.  Morton 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 0-613,  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 VI-29.
     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.
     Norton 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
                                     139

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TABLE VI-29.  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
Treatment (Doses/week - mg/Dose)
D-l

n-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 naphthalene
and 15% benzene
solution
2-1
2-50
3-100
2-10
2-10
2-10


3-50
3-50
2-15
2-50



Mean Time-to- PMC*
Tumor (weeks)
15. 6t
12. 6t
7.0t
24.8
23.6
25.1


21.9
17.1
33. Ot
30. 6t


iT* i n -t-vio Dwr
0.27t
0.37t
0.63t
0.13
0.14
0.13


0.11
0.16
0.08t
O.lOt


•inrre3<;p<; as
carcinogenic potency increases.

   tThe multiple doses for Tars D-l and D-613 demonstrated a mean
tumor and a PMC dose-response.
                                                                 time-to-
                                    140

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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 benzo[a]pyrene content of the test

 substances are reported in Table VI-30.

    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-30.  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 Horton 1961)
Test Material
Tar D-l
Distillate Oil of
Doses (mg)
20
10
Content of
Benzo[a]pyrene (%
0.74
0.01
Relative Carcinogeni
) Potency (PMC)
0.27
0.01
c


  Tar D-l

Proportionate Reblend    10
  the Nine Cuts of
  Tar D-l

Carbolic Oil  of Tar
  D-9                    10

Light Creosote Oil        10
  of Tar D-9
0.08




0.00

0.00
0.11




0.00

0.00
                                     141

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    Wallcave 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 tumorigenic effects observed.
                                      142

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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 most1epithelial 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-31  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).

j)ocarcinogens
    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,
                                     143

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TABLE VI-31.
                       POLYCYCLIC ORGANIC MATTER (POM)  IDENTIFIED IN
                            COKE OVEN EMISSIONS*
Compound
                                 Animal Carcinogenicityt
                              IARC                    CAG
Anthracene
Benz[a]anthracene
Oi benz[a ,c]anthracene
Methylphenanthrene
Phenanthrene
BenzoCc]phenanthrene
Benzo[a]fluorene
Benzo[b]fl uorene
Dihydrobenzo[a]fl uorene
Dihydrobenzo[b]fluorene
Dihydrobenzo[c]fluorene ง
Fluoranthene
Benzo[c]fluorene
Benzo[b]f1uoranthene
Benzo[j]f1uoranthene
Benzo[k]f1uoranthene
Benzo[ghi]f1uoranthene
Pyrene
Methylpyrene
Benzo[a]pyrene
Benzo[e]pyrene
Dibenzopyrenes
Chrysene ง
Triphenylene ง
Perylene
Benzo[ghi]perylene ง
Anthanthrene ง
Coronene
Acridine
Benzoquinoline
Octahydrophenanthrene
Octahyd roanth racene
Dihydrofluorene
Benzindene
Fluorene
Dihydrophenanthrene
Dihydroanthracene
Methylfluorenes
Fluorene  Carbonitrile
Methyl anthracene
Ethylphenanthrene
Ethyl anthracene
                                              (continued on the following  page)
                                      144

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                             TABLE  VI-31.   (continued)
Compound
   Animal
I ARC
Carci nogeni ci tyt
                                                                     CAG
Octahydrofluoranthene ง                      ?
Octahydropyrene ง                            ?
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 ง                  7
Dihydrochrysene ง                            ?
Dihydrotriphenylene ง                        ?
Dihydromethylbenz[a]anthracene ง             ?
Dihydromethylchrysene ง                      ?
Dihydromethyltriphenyl ene ง                  ?
Methyl benz[a]anthracene                      4^
Methyltriphenylene                          T
Methyl chrysene                            .   +_
Dihydromethylbenzo[k and b]-                ~
 fluoranthenesง                              ?
Dihydromethylbenzo[a and e]pyrenes ง         ?
Dimethylbenz[a]anthracene ง                  +                         +
Dimethyltriphenyl ene ง
Dimethylchrysene ง                           +
Methylbenzo[k]fluoranthene ง                 ?
Methylbenzo[b]fluoranthene ง                 ?
Methylbenzo[a]pyrene                         +
Dimethylbenzo[k and b]-
 fluoranthenes                               ?
Dimethylbenzo[a]pyrene                       +
o-Phenylenepyrene                            ?
Methyldibenzanthracene                       +
Methylbenzo[ghi]peryl ene                     ?

    *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

    Confirmation  of chemical structure questionable in Lao et al. (1975).
                                     145

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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.
                                     146

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                          VII.  QUANTITATIVE ESTIMATION
 INTRODUCTION
      This quantitative section deals with the unit risk for coke oven emissions
 in air and the potency of coke oven emissions relative to other carcinogens  that
 the CAG has evaluated.  The unit risk estimate for an air pollutant is defined as
 the lifetime cancer risk occurring in a population in which  all  individuals
 are exposed continuously from birth throughout their lifetimes  to a concentration
 of 1 ug/m3 of the agent in  the air they breathe.   This  calculation  is  done to
 estimate in quantitative terms the impact of the  agent  as  a  carcinogen.   Unit
 risk estimates are used for two purposes:  1)  to  compare the carcinogenic
 potencies  of several  agents with  each other,  and  2)  to  give  a crude  indication of
 the population risk that  might be  associated with  exposure to these  agents, if
 the actual  exposures  are  known.
      The data  used for the  quantitative  estimate  can  be of two types:  1) life-
 time  animal  studies,  and  2)  human  studies where excess cancer risk has been
 associated with exposure  to the agent.   It is  assumed, unless evidence exists
 to  the contrary, that  if  a  carcinogenic  response occurs at the dose levels used
 in  a  study,  then  responses  will occur at  all lower doses with an incidence
 determined by the extrapolation model.
      There is  no solid scientific basis  for any mathematical  extrapolation
model that relates carcinogen exposure to cancer risks at  the extremely low
concentrations which must be dealt with  in evaluating environmental  hazards.
For practical reasons, such  low levels of risk cannot be measured directly
either by animal experiments or by epidemiologic studies.   We must,  therefore,
depend on our current  understanding of the mechanisms of carcinogenesis  for
guidance as to which risk model to use.   At  the present  time, the dominant
                                      147

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view of the carcinogenic process involves the concept that most agents  that
cause cancer also cause irreversible damage to DNA.   This  position  is reflected
by the fact that a very large proportion of agents that cause  cancer are  also
mutagenic.  There is reason to expect that the quanta!  type of biological
response, which is characteristic ,of mutagenesis,  is associated with a  linear
non-threshold dose-response relationship.  Indeed, there is substantial evidence
from mutagenesis studies with both ionizing radiation and  a wide variety  of
chemicals that this type of dose-response model  is the appropriate  one  to use.
This is particularly true at the lower end of the  dose-response curve.  At higher
doses, there can be an upward curvature probably reflecting the effects of
multistage processes on the mutagenic response.   The linear non-threshold dose-
response relationship is also consistent with the  relatively few epidemiologic
studies of cancer responses to specific agents that  contain enough  information
to make the evaluation possible (e.g., radiation-induced leukemia,  breast and
thyroid cancer, skin cancer induced by arsenic in  drinking water, liver cancer
induced by aflatoxins in the diet).  There is also some evidence from animal
experiments that is consistent with the linear non-threshold model  (e.g., liver
tumors induced in mice by 2-acetylaminofluorene  in the large scale  EDgi study
at the National Center for Toxicological  Research  and the  initiation stage of
the two-stage carcinogenesis model  in rat liver  and  mouse  skin).
     Because of these facts, the linear non-threshold model  is considered to be
a viable model  for any carcinogen, and unless there  is direct  evidence  to the
contrary, it is used as the primary basis for risk extrapolation to  low levels
of exposure.
     The quantitative aspect of carcinogen risk  assessment is  included  here
because it may be of use in the regulatory decision-making process,  e.g., in
setting regulatory priorities, evaluating the adequacy of  technology-based

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controls, etc.  However, it should be recognized that the estimation of cancer
                                                                           •a
risks to humans at low levels of exposure is uncertain.  At best, the linear
extrapolation model used here provides a rough but plausible estimate of the
upper limit of risk, i.e., it is not likely that the true risk would be much
more than the estimated risk, but it could very well be considerably lower.
The risk estimates presented below should not be regarded as accurate
representations of the true cancer risks even when the exposures are
accurately defined.  The estimates presented may, however, be factored into
regulatory decisions to the extent that the concept of upper risk limits is
found to be useful.
ESTIMATION OF THE UNIT RISK—CONSIDERATIONS
The Need to Employ Mathematical Models, and the Errors They Introduce
     To estimate a unit risk directly, one would need a cohort of individuals
exposed from birth to death to 1 ug/m3 of coke oven emissions.  The estimate
of the unit risk would then be the observed number of respiratory cancer deaths
in the cohort minus the expected number of respiratory cancer deaths divided by
the number of individuals who were originally in the cohort.   The expected
number of respiratory cancer deaths would be based upon an  equivalent nonexposed
population.  Obviously, no such ideal  situation will  ever exist for a human
population.
     To estimate the unit risk from human data, we must make  use  of the  information
contained in epidemiol ogic studies.  Typically, epidemic! ogic studies involve
workers whose exposure started and stopped at different ages  and  fluctuated  over
time due to changes in job classification and working conditions.  Also,  workers
enter the cohort under observation for cancer mortality at  different ages and are
followed for different lengths of time (usually less  than their full  lifetimes).

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     In order to use this type of fragmented information to predict lifetime
cancer mortality due to lifetime environmental  exposures, it is necessary to
postulate a mathematical  relationship between the future age-specific cancer
death rate and the past exposure pattern.  Once this relationship is established,
it can then be used to estimate the unit risk by a well-known mathematical
technique.
     The use of a mathematical relationship or model, although necessary, introduces
several major sources of potential  error in the estimation of risk.  All  such
models contain unknown parameters that must be estimated from the data obtained
from epidemiologic studies.  The parameter estimates are variables that may
differ from the true unknown parameter values by amounts that are large enough
to alter estimates of risk considerably for low levels of exposure.  To express
the plausible range of risk associated with an assumed mathematical model, con-
fidence bounds on the risk are obtained.  These bounds are values between which
we have a specified degree of confidence that the true unknown risk lies.  However,
the accuracy of these derived confidence bounds depends upon how well the assumed
model corresponds to the true dose-response relationship.
     The mechanisms by which a chemical induces cancer are not presently understood.
As a result, it is not possible to derive any mathematical model  that relates
exposure to cancer rate with a high degree of plausibility.
     The difference between the assumed dose-response relationship and the true
unknown response constitutes an additional source of error in estimating risk.
This source of error, however, is not very great if the levels of exposures on which
a risk estimate is desired are near the levels of exposure which existed in the
epidemiologic study from which the dose-response model is derived.  In such a
case, the confidence bounds constitute a reasonable approximation of the total
uncertainty.  However, as the difference between the two exposures increases, the

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 uncertainty  associated  with  the  difference  between the  assumed and actual dose-
 response model  increases  rapidly, and eventually exceeds all other sources
 of  uncertainty.
      The next  section discusses  some of the general factors that should be
 considered in  selecting a form for the mathematical model to be used to
 generate unit  risk  estimates.

 Selecting a  Form of a Model  for  the Age-Specific Exposure-Induced Respiratory
 Cancer Death Rate"       ~~~                                     ~~
      A number  of general principles, some of which stem from the logical
 basis of scientific method,  are  relevant in deciding how to select a model to
 describe the age-specific exposure-induced cancer death rate.

 The Model Should Conform to the  Observed Data Set--
      For any set of data there exists an infinite number of mathematical models
 that  can give predictions which  fall within the limits of the random error
 associated with the data.   Some  of these models fit the data better than others.
 Hence, there is a temptation to  select the model that  gives the "best fit" as
 the one to use in making risk predictions.  The trouble with this approach is
 that the "best-fitting model" selected in this manner  is itself a random variable.
 A small change in the data could alter what was defined as  the "best-fitting
model."  If the predictions of risk relate to exposures that fall  within the
 range of the experimental  data used to derive the model, it is of little practical
consequence which of the adequately fitting models  is  used.   However,  the  choice
of model  becomes critical  when one attempts to extrapolate  far beyond the  range
of the experimental  data.   Two models  that give an  adequate fit to  the data  in
the experimental range can give answers  that differ by many orders  of magnitude
for environmental  levels of exposure.
                                      151

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     To illustrate this point, consider the following hypothetical  but  typical
example.  Assume that an experiment was run at  three  dose  levels,  plus  a control
level, and that the results were as shown in Table VII-1.

                    TABLE VII-1.  HYPOTHETICAL  BIOASSAY  DATA
Test Group
Number
(J)
1
2
3
4
Exposure Level
mg/kg
(Xj)
0
1.0
1.4591
2.0176
Number of Site-
specific Tumor Deaths

-------
 where b1 is arbitrarily fixed at 0.01,  and b* is  the maximum  likelihood  estimated
                                             O
 value of the cubic term for b]^ = 0.01.   The maximum  likelihood  solution  for the

 cubic term in this case is  b* = 0.2188,  so that
                             O

                                 -(O.Olx,  + 0.2188X,3)
                          PAJ  = e                     .

      The resulting risk obtained for  the  two models  for the experimental exposure

 levels  and three  low  environmental exposure levels are compared in Table VII-2.
      TABLE  VII-2.   PREDICTED  RISK  LEVELS USING MAXIMUM LIKELIHOOD MODEL AND
                              AN ALTERNATIVE MODEL
Exposure
X
2.0176
1.4591
1.0
0.1
0.01
0.001
PO
0.84000
0.50000
0.20000
2.23 x ID'4
2.23 x 10-7
2.23 x 10-10
PA
bj = 0.01
0.83752
0.50056
0.20451
1.22 x 10-3
1.00 x 10-4
1.00 x ID-5
Observed Result
r/n
0.84
0.50
0.20



     The maximum likelihood fit is slightly better in the observed range,  and

the estimates of risk in the environmental  range are much smaller for the

maximum likelihood model.  If the maximum likelihood model  is used to predict .

risk, it should have some meaningful  measure of superiority over  the  alternative

model.   This measure of superiority is expressed as  the relative  likelihood  or

odds ratio R.  It is found that the odds  ratio in this  case is  R  = 1.0043.   Thus
                                      153

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the maximum likelihood is 0.43% more likely than the alternative  model.   This
slight superiority of the maximum likelihood model  is of  a  lesser magnitude
than many other differences that are generally perceived  as insignificant.   For
example, assume that upon revaluation of the pathological  data,  one  of  the
positive tumors in the high-dose group is considered not  to be  a  tumor after
all, and that there are thus 41 rather than 42 tumors in  the high-dose group.
If our previous models were evaluated with the new  data set, the  results obtained
would be R = 0.9861.
     Therefore, even a minimal  and highly plausible change  in the data set would
change the relative risk so that the alternative model  would have a  1.42% greater
odds than the original maximum likelihood model. Alternatively,  if  the  probability
is 0.232 or better that one or more of the originally diagnosed tumors in the
high-dose group is not a tumor, then the alternative model  would be  more likely
to be correct than the original maximum likelihood  model.
     As the foregoing examples have indicated, the  maximum  likelihood model  cannot
be regarded as a very prudent method of estimating  risk at  low exposure  levels,
especially when the experimental evidence indicates that it is almost as likely
that the risks are five orders of magnitude higher.  We cannot simply use the
best-fitting model to obtain our risk estimates without having the potential for
seriously underestimating the true risk.
     Nevertheless, it is still important that the model chosen be consistent
with the observed data.  It is impossible to prove  that a model is correct or
incorrect on the basis of observed data.  All that  can logically be  said is
that if the model is correct, then a departure from the predicted .results as
large or larger than the observed results would occur with  a probability of  P
or less.  As a matter of convention, a critical value a is  chosen.  If the
observed departure value P is less than ซ, the data are deemed inconsistent

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with the model, and the model is rejected from further consideration.  The
value a is frequently set at 0.05.  However, this is strictly arbitrary.  If
the consequences of discarding a model when it is true are quite grave, a might
be set at 0.01 or even a smaller quantity.  Also, P is often obtained from a
statistical test based on a number of approximations and/or assumptions.  In
this case, it is important to evaluate whether the data set is of sufficient
size to assure the validity of the approximations upon which the test is based.
     A large data set will have the ability to discriminate between a number of
models, rejecting some and accepting others.  However, no matter how large a data
set is, there are still  an infinite number of potential models that would be
consistent with the observed data.  It is clear that other criteria for selecting
a model need to be considered in order to narrow the range of potential  models.

The Model  Should Be Based Upon an Acceptable Biological Theory that is Consistent
with Known Facts--
     Ideal ly, one would use only models derived either from an underlying biological
theory that had wide acceptance or from a new theory constructed from a set  of
logically acceptable principles.  The problem is that of  defining what constitutes
"wide acceptance" and "logically acceptable principles" in the area of the
mechanisms of cancer response.

The Model  Should Be As Simple As Possible--
     All  other things being equal, a principle often used to decide among
theories  is that of "Occam's Razor" (Cohen 1931).  Occam's Razor expresses
the proposition that nothing extraneous should be part of a theory, or that  a
model  should be as simple as possible.  Although it is not always clear what
is meant  by "simple," the word may logically be interpreted to mean "requiring
as few parameters as possible to adequately describe the  data."
                                      155

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Special Considerations for Particular Applications of the Model
      In selecting a model for practical use, the consequences of selecting the
wrong model must also be considered.  In our case, the use of a model that
underestimates the true risk could result in a decision with a serious impact
on human life.  To guard against that possibility, we tend to be conservative.
This means that unless there is specific, explicit information to the contrary,
we will use the model that gives the highest risk at environmental  levels of
exposure, subject to the constraints that the model have an acceptable scientific
basis and be consistent with the observed data.  Therefore, our estimates
should be viewed as plausible upper bounds of risk.  It is possible that the
actual risk may be far lower than we predict.  The true risks may be virtually
zero at low doses where different mechanisms controlling dose-response may come
into play.  One could also obtain estimates of risk with a variety  of other
models that fit the data in the observed range, and that have acceptable scienti-
fic bases.  However, since such estimates would lie between zero and our upper
bound, they would not supply any additional  information on the true risk, nor
would they have any other practical  use.
     Another practical  consideration is that the unit risk numbers  generated
will  be used in a relative sense for comparison of different environmental
hazards.  To assure meaningful  comparisons,  the techniques and assumptions  used
to generate the models  should be as consistent as possible.  This consistency
should also be maintained between animal bioassays and human epidemiologic
studies.
     A large number of  mathematical  models relating exposure to cancer risk may
be postulated.  However, the models that can be applied to the coke oven data are
highly restricted by the form of the available data.   In the next section,  the
data  base available for obtaining a unit risk estimate is discussed.

                                      156

-------
DATA BASE AVAILABLE FOR THE ESTIMATION OF UNIT RISK
     The best source of information available for estimating the unit risk due
to coal tar pitch volatiles is a series of epidemiologic studies that followed
the mortality experience of steelworkers who had worked or were working around
coke oven batteries.  Lloyd et al. (1970), Lloyd (1971), Redmond et al. (1972)
and Redmond et al. (1976) obtained mortality data for a cohort of coke  oven
emission-exposed steelworkers over a 15-year period.  Mazumdar et al. (1975)
used monitoring information collected and reported by Fannick et al .  (1972) on
worker exposure in Pennsylvania in the 1960s to estimate exposure levels for
various job classifications.  Mazumdar et al. then used these job classification
exposure estimates in conjunction with the working histories of the cohort
followed by Redmond et al. to obtain an exposure profile for each individual  in
the cohort.
     Land (1976) sorted the data assembled by Mazumdar et al. into 12 age
groups at the beginning of the observation period*  Each age group was  stratified
into a number of exposure intervals where exposure was in units of mg/m^ x months.
The exposure units were obtained by multiplying the air concentrations  of coal tar
pitch volatiles times duration of employment.
     Land also calculated the same type of summary data under the condition that
any exposure that occurred within a specified "lag time" from a year  of observa-
tion was not included in the cumulative exposure total  for that year.  The
exposure data compiled by Land is shown in Tables VII-3 and VII-4.   Table VII-3
shows the data for the controls, and Table VII-4 shows the data for the cohorts
exposed to coke oven emissions.
     The unit risk estimates in this document are based on the information gen-
erated by Land (1976).  This choice was dictated by the circumstances.   It would
have been preferable to use as our data base the Redmond et al. (1979)  study,

                                      157

-------
which updates the mortality experience of the coke  oven-exposed  population  to

1976.  This would give more person-years of observation  for  analysis  of  black

workers, and also would allow the use of the respiratory cancer  mortality

experience of white workers, which had become statistically  significant  by  this

time.  Unfortunately, the exposure analysis has not been extended  beyond 1966.

As a result, the decision was made to use the more  limited mortality  data,  up

to 1966, with an extensive exposure analysis, rather than the  more complete 1976

study which had, by comparison, very limited exposure information.
      TABLE VII-3.  LUNG CANCER MORTALITY EXPERIENCE OF  NONWHITE COKE  OVEN
                          WORKERS COMPARED TO CONTROLS
                                  (Land 1976)

Age at
Entry
<20
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70+
Total


Popn*
343
779
869
700
601
560
458
409
301
148
48
11
5227
Controls

Casest
0
0
1
2
1
3
8
9
3
1
0
0
28

Person-years
/ of Observation
4633
11027
12387
10018
8487
7740
6187
5119
3651
1607
455
107
71418
     *Number of individuals in the cohort at the start  of  the  observation
      period.
     tNumber of respiratory cancer deaths over the observation period.
                                      158

-------
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       It would also have been preferable  to use Mazumdar's  original  data  set,
  which contained  the entire  exposure  pattern,  length  of  follow-up  period,  and
  vital  status  for each  individual  in  the  cohort.   This would  have  made  it  possible
  for  various age-specific  dose-response models  to  be  fitted to the data in a way
  that accounted for both the  timing and the  level  of  exposure in a mathematically
  optimum manner.   However, time and resource constraints precluded that option
  for  at  least  the  short  term.
      As a result,  our analysis had to be based upon the summary data generated
  by Land (1976).   This data set contains little information on the timing of
  exposure and death.  It also has a number of other limitations  and problems
  associated with it.  These will  be discussed in more detail  later in this
 document in conjunction with discussions  of specific mathematical  models.
 However, the advantage of this data  set  is  that it still  contains  far more
 extensive information about  the  relationship between exposure and  mortality
 than  is presently available  for  any  other study on coke  oven  emissions.
      In the  next  section,  the methods used  to  obtain  estimates of  the parameters
 for the age-specific exposure-induced respiratory  cancer death rate  models
 from  the Land  data are outlined.   Some of the  problems associated  with  using
 the data  in the form given by Land are also  discussed.

 AGE-SPECIFIC EXPOSURE-INDUCED RESPIRATORY CANCER DEATH RATE MODELS
 Detailed Discussion  of the Exposure Parameter Compiled by Land (1976)
      In order to have an appreciation of some of the problems  associated with
 using the data base assembled by Land (1976), it is necessary  to  understand exactly
 how the exposure parameter was computed.   The exposure variable  calculated by
 Land for each individual  in the cohort is  the I-year lag-time-adjusted cumulative
average exposure over the observation  period.  This variable can  be obtained  in

                                      177

-------
the following manner.   For a given year in the observation  period,  the total
mg/fa3 x months of exposure is calculated up to that point  in  time.   The  I-year
                                                                           o
lag-time adjustment is made by subtracting from the total  exposure  the mg/m  x
months of exposure that occurred within the last I years.
     The I-year lag-time-adjusted exposure evaluated at the ttn year may be
expressed in mathematical terms by the relationship
                                        t-I
                                            x(s)ds
where x(s) is the instantaneous exposure rate at time s.
     This calculation is done for each year the individual was under observation
in the mortality study.  The average of these yearly values is the I-year lag-
time-adjusted average exposure for the individual.  The actual value shown by
Land for each of the exposure-age cells in Table VI 1-4  is the average for all
individuals  in the  cell  of  their  I-year lag-time-adjusted average exposure.
     The rationale  for  the  lag-time  adjustment  is clear.  It  is known for many
carcinogens  that the initializing event which ultimately  results in a tumor death
can  occur many years prior  to the death.   This  has been shown to hold in such
varied  cases as:
      (1) leukemia,  respiratory,  and  other  cancers due to  atomic bomb radiation,
      (2)  respiratory  cancer due  to  smoking cigarettes,  and
      (3) mesotheleomia  due  to  asbestos  exposure.
 If the  carcinogen's primary action  is  on  early  events  in  the  carcinogenic  process,
 then the likelihood that a  particular  exposure  causes  the death diminishes  as
 the time of death approaches.   In this  case,  to consider  all  exposures  of  the
 same magnitude to have the same  effect  regardless  of when they  occurred would
 give a distorted picture of the  true dose-response  relationship.
                                       178

-------
      To correct  for this  possibility,  Land made  the  simplest  possible type of
 lag-time or  latency period  adjustment.   He assumed that  for an  exposure to have
 an effect,  it must have occurred  at  least  I years prior  to the  time of death.
 If the  exposure  occurred  I  years  prior  to the time of observation, it was given
 full  weight;  if  it did not,  it was given no weight.  Since the  length of the
 lag time was  unknown,  various lag times were selected that were typical of the
 observed latency periods  in  other known situations.
      This simple approach would more closely approximate the true dose-response
 relationship  if  the underlying assumption of a true  latency period was valid.
      It would  be desirable  to see which lag-time assumption gave the best fit
 to the  observed  data.  Unfortunately, due to Land's  way of organizing the data,
 it is not possible  to make  a valid comparison between lag-time assumptions.
 For the comparison  to be valid, the same individuals would have to remain in   ,
 the exposureage  cells with their  exposure variable changing due to lag time.
 For the most  part,  as seen  in Table VII-4,  this was  not done.   The exposure
 intervals were held constant and  the number of cases in each  exposure-age cell
 varies  as the  lag time changes.    These changes result in a change  in  the  "infor-
 mation  content"  of the data sets.  As a result, it is impossible to determine
 how much of the  total information gain is due to reorganizing  the  data, and how
 much is due to a better fit.
     Therefore, one assumption of lag-time  length cannot  be chosen over another
 on the  basis of the available data.   Other  types of  lag-time adjustments  that
 give different weights for exposures  at different lengths of time  from the
 observation  period might  have been preferable,  but data  of  that  nature has yet
to be  assembled.
     Given these  constraints, each lag-time assumption  given in  Table VII-4   '
will be used to estimate  risks separately,  and  the varying  results  due to

                                      179

-------
lag-time differences will be regarded as simply another source of potential
error.

Specific Mathematical Models
     Two different general mathematical forms will be assumed for relating
exposure to induced cancer death rate.  Each form is analogous to a mathematical
model commonly used to obtain risk estimates from animal  bioassay data, and
each has various advantages.

"Weibull" Type Model--
     The type of model with the fewest parameters that will adequately fit the
data in Table VI1-4 is "Weibull" in form.
     It is assumed that the increase in the exposure-induced cancer death rate
is proportional to the lag-time-adjusted cumulative exposure raised to some
unspecified power.  This may be expressed as

                                 r(t) = AX(I,t)m

where r(t) is the exposure-induced cancer rate at time t; A and m are unknown
parameters to be estimated from the data; and X(I,t) is the lag-time-adjusted
cumulative exposure previously defined.
     In order to estimate A and m from the available data, a number of simplify-
ing assumptions need to be made.  It is assumed that the  exposure-induced
cancer death rate is constant over the observation period for each of the
exposure-age cells.  This increased constant rate is assumed to be predicted by
the Heibull relationship, where the exposure is the average I-year lag-time-
adjusted cumulative exposure for an exposure-age cell shown in Table VI1-4.
                                      180

-------
      The increased exposure-induced cancer death  rate  in  each  cell  is  estimated  by
 dividing the estimated increase  in  the  number  of  respiratory cancer  deaths  by the
 person-years of observation.   This  relationship may  be  expressed as

                                     r = 0-E
 where  0 is the  observed  number  of  respiratory cancer deaths, and W is the person-
 years  of observation,  both  of which  are  given in Table VI1-4 for each of the
 exposure-age  cells.  The  value  E is  the  expected number of respiratory cancer
 deaths  in an  exposure-age cell  under the assumption that the exposure had no
 effect  on the respiratory cancer death rate.
     The values  of E are estimated by assuming that the same background res-
 piratory cancer  death  rate exists for the exposed population as was observed in
 the control population of comparable age.  However, to obtain more stable
 rates,  the control populations for different age groupings were combined, and
 this combined estimate applied to more than one age grouping.   Table VII-5
 shows how these combined estimates were obtained and the subgroups  to which
 they were applied.  The expected number of respiratory cancer deaths in the
 absence  of an exposure effect is thus calculated by multiplying the person-years
 of observation in the exposure-age cell  by the corresponding estimated background
 rate given in Table VII-5.  Thus E = Wr0 for each  cell,  and the estimated
 increased respiratory cancer rate is
                                       0-Wr
                                   r =
                                           o.
This increased rate is then equated to the average I-year  lag-time-adjusted
cumulative exposure given in Table VII-4,  which  we denote  as  X(I).   Assuming  a
Weibull-type relationship between the variables,  we obtain  the  relationship
                                      181

-------
                                  0-Wr
                                      o _
= AX(I)r
which may also be expressed as
                               0 = W[rQ + AX(I)m]
       TABLE VI1-5.  CALCULATION OF ASSUMED BACKGROUND RESPIRATORY CANCER
                           DEATH RATES FROM DATA IN TABLE VII-4
Age at
Entry

<30
30-39
40-49
50-59
>60
Observed
Cases
0
1
3
11
12
1
Person -years
VJ

28,047
18,505
13,927
8,770
2,169
Estimated
Background Rate
r = 0/W
3.5654 x ID'5
1.6212 x 10-4
7.8983 x 10-4
1.3683 x 10-3
4.6104 x 10-4
 The assumption  is made  that  the  observed  number of cases is a Poisson random
 variable with a mean  equivalent  to the  right side of the previous equation.
 Under this assumption,  the maximum likelihood estimators of A and m are obtained
 for each of the four  lag times.   In  addition, a 95% confidence interval is
 obtained for the parameter m,  which  will  be the critical variable in the estima-
 tion of risk at low exposures.  The  results of these calculations are shown in
 Table VII-6.
      A wide variability is  noted in  the power parameter m,  ranging from
 slightly larger than  a cubic model  for  the upper-bound zero lag,  to  slightly
 larger than a linear model  for the  lower-bound  15-year lag. Also, within  a
 single lag time, the power parameter will vary  by more than one  full  unit  of
 power.
                                       182

-------
              TABLE VI1-6.  ESTIMATED PARAMETERS FOR "WEIBULL" TYPE
            MODEL FOR EACH LAG-TIME ASSUMPTION WITH CONFIDENCE LIMITS
Lag Time
I
0
5
10
15
-— — •—— -~-- — —i———— ———— — -,
*u.b. - upper
estimate.
Function of
Parameter m*
95% u.b.
m. I.e.
95% l.b.
95% u.b.
m. I.e.
95% l.b.
95% u.b.
m. I.e.
95% l.b.
95 u.b.
m. I.e.
95% l.b.
bound; l.b. = lower
Value of
Function
3.03
2.37
1.80
2.62
2.07
1.60
2.29
1.66
1.15
1.80
1.39
1.03
bound; m. I.e.
A Value
Associated with
Corresponding
m Function
l.OOxlO-11
7.60x10-10
2.86xlO-8
2.55x10-10
8.54xlO-9
8.43x10-8
8.82x10-10
9.21x10-8
1.86xlO-5
1.28x10-7
1.39xlO-6
l.OOxlO-5
= maximum likely
     This statistical variability in the power parameter will translate into wide
variability in risk estimates.   In addition, there is a serious drawback in using
the Weibull model with its statistical limits of error to predict the probable
range of risks.  That approach does not in any manner account for the potential
deviation of the Weibull model from the true but unknown dose-response relation-
ship.
     Numerous factors indicate that the Wei bull  model may not be .the true dose-
response model at low environmental  levels of exposure.   The observed Wei bull-type
relationship could possibly be an artifact of how the data was arranged rather
than the true shape of the dose-response curve.   This would be the case if total
                                      183

-------
exposure were positively correlated with length of exposure,  and if exposures
in the past had more effect than exposures near the observation period.
     Under the Wei bull  model, where exposure is constant and  continuous  at
level x, i.e., x(s) = x  o I
so that the exposure-induced cancer rate at time t is

                          r(t) = A [x(t-I)]m = Axm(t-I)m.

     Thus, the Wei bull model predicts that exposure rate and length of exposure
corrected for a latency will have the same power m.  This result is in direct
contradiction to most of the observed relationships for both experimental  animal
bioassays and human epidemiologic studies.
     The true shape of the dose-response relationship at high dose levels  may
be different from the true shape at low dose levels due to different carcino-
genic mechanisms, absorption rates, etc.  For example, the elimination of  a car-
cinogen from the body may be much more efficient at low doses than at high doses,
resulting in a virtual threshold.  On the other hand, low exposures may be
dose-additive with other carcinogens of much greater magnitude.   In this case,
the added risk due to coke oven emissions at low doses would be linear regard-
less of the shape of the dose-response curve at high doses.
     To allow for the possibility that the error limits placed upon the
Weibull model underestimate the true potential range of risk, a "multistage"
type model was also considered to be a viable alternative.  This model is
discussed in the next section.
                                      184

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 "Multistage" Type Model--
      It is assumed that the increase in the exposure-induced cancer death rate
 may be expressed as a third degree polynomial  in lag-time-adjusted cumulative
 exposure.  The results using the Weibull model  indicate that a higher degree
 polynomial would not be needed.  Under this assumption, the exposure-induced
 cancer death rate has the form
                                       b2X(I,t)2 + b3X(I,t)3
 where bj, b2,  and b3 are unknown parameters  greater  than  or  equal to  zero to be
 estimated from the data.  These parameters are  estimated  in  the  same  manner
 as  in the "Weibull"  case by  equating  the  estimated increased exposure-induced
 cancer rates to the  right side  of the previous  equation.
      The  upper-bound risk associated  with this model is obtained in a manner
 analogous to the approach used  by the Carcinogenic Assessment Group (CAG) to
 obtain  the upper bounds  on risk  using  the multistage model and animal  bioassay
 data.   The rationale for using that approach is given in the EPA Water Quality
 Criteria  Document  (U.S.  EPA  1980o), and the mathematical derivation is found in
 Crump  (1981).
      One  of the  main  advantages to finding the upper bound in this manner is
 that  it takes into account simultaneously both statistical variability in the
 parameter estimates  and  variability resulting from the lack of knowledge of  the
 true functional  form of the dose-response relationship.   This approach assumes
 that  low-dose linearity  is a viable possibility  and that it is  also  a  reasonable
 upper bound on  the dose-response in the unobservable  range.   Using this  approach,
 the polynomial  with the largest linear term that is not  statistically  significantly
worse than the  best-fitting polynomial is  obtained.
                                      185

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     In Table VII-7, the best-fitting polynomial  and the upper-bound  polynomial

with the largest linear term are shown for each  of  the  four  lag-time  adjustments.
        TABLE VII-7.  THE MAXIMUM LIKELIHOOD ESTIMATES OF THE  PARAMETERS
           IN THE MULTISTAGE MODEL AND THE 95% UPPER BOUND POLYNOMIAL
                      FOR EACH I-YEAR LAG-TIME ASSUMPTION
Lag-time
I
0
5
10
15
*m.l .e.
Model*

m.l .e.
95% u.b.
m.l .e.
95% u.b.
m.l .e.
95% u.b.
m.l .e.
95% u.b.
= maximum 1 i
bl

2.00xlO-6
0
3.25X10-6
3.00x10-6
7.04x10-6
6.46X10-6
1.30X10-5
kely estimate;
b2

. 4.90X10-9
0
1.22X10-8
0
l.OSxlO-8
0
1.83xlO-8
0
u.b. = upper
b3

4.96X10-12
7.33X10'12
l.SlxlO-12
l.llxlO-11
7.41X10-12
1.24X10-11
0
9.24xlO-12
bound.
     The next section discusses the method by which the exposure-induced cancer

 rate function r(t) is transformed into an expression relating the lifetime cancer

 risk due to a lifetime constant exposure in ug/m3.



 ESTIMATION OF LIFETIME CANCER RISK DUE TO A CONSTANT LIFETIME EXPOSURE

     The exposure  units used in the derivation of the induced cancer death rate

 function r(t) were in mg/m3 x months over the working day.  The first step in

 deriving the  lifetime rate is to transform ug/m3 of continuous exposure into

 exposure units equivalent to those used in the epidemiologic study.  This may

 be  done by multiplying exposure rate x in ug/m3 by a constant C where
                                      186

-------
                       c =
= 10-3 x 12 x 24 x 365 = 0>Q5475
                                            240
is the cumulative exposure in mg/m3 x months one would obtain in a year by
working 8 hours/day, 240 days/year in an area containing 1 ug/fa3 of the agent
in the air.  This is equivalent to the same cumulative exposure that would be
experienced in an area containing 1 ug/m3 of the agent in the air continuously
for a year.
     Under the assumption of a constant exposure at level x ug/m3, the  exposure
rate function x(s) is
                              x(s) = Cx     o< sO

and the I-year lag-time-adjusted exposure is

                                 t-I
                        X(I,t) =  /   Cxds = Cx(t-I).
                                  o

     Thus the induced cancer death rate functions  r(t) due to a continuous  ex-
posure rate of x ug/m3 may be obtained by substituting the equivalent term  for
X(I,t) into the cancer rate equations.   This gives  the results
                     r(t) =
                              0
                              A [Cx(t-I)]
                                         m
for the Wei bull-type model,  and
                                3ฐ
                         p(t)  = Z  bj[Cx(t-I)]J    t> I
for the multistage-type model.
                                      187

-------
     Given the exposure-induced cancer death rate function r(t), the lifetime
risk may be calculated directly using the methods described by Chiang (1968)
and Gail (1975).  To do so, it is necessary to specify the total age-specific
death rate function in the absence of exposure.  This function is denoted as
h(t).
     The lifetime risk is calculated by obtaining the risks of dying of cancer
caused by the exposure at each instant in time and summing them over all  possible
times.   The probability of dying of exposure-induced cancer at time t is  the
probability of living until time t times the exposure-induced cancer death rate
function at time t.   The total death rate from all causes at time s is
r(s) + h(s).   Thus,  by definition the probability of surviving until
time t, S(t), is
                     S(t) = e o
                                 [r(s)+h(s)]ds
     The probability of death due to exposure-induced cancer at time t, P(t),  is
                           P(t) = r(t)S(t)
and the lifetime probability of death due to exposure-induced cancer is
                                    oo       -f  [r(s)+h(s)]ds
                    P = /  P(t)dt = /  r(t)e o
                        o           o
     The lifetime risk is calculated using this relationship for both the Wei bull
and the multistage models and their statistical bounds, assuming a constant
exposure of 1 ug/m^.
     Two assumptions are used concerning the total age-specific death rate h(t).
The first is that the total age-specific death rate is the same as the total  age-
                                      188

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 specific  death  rate  for  nonwhite males.   The  resulting risk is interpreted to

 be  for black males,  and  the assumption is made that it would be equivalent for

 every other member of the population.  The second assumption is that h(t) is

 the same as for the  total population.  This implies that the exposure-induced

 cancer death rate for black males is the same as for all  other members of the

 general population.  The resulting risk under this assumption  is  the average

 for a member of the  general  population.  The data used to calculate these risks

are the 1978 vital  statistics  for the United States,  which are  the  most  recent

available.  The results  of these calculations  are shown  in Tables  VII-8  and

VII-9.
       TABLE VII-8.   LIFETIME PROBABILITY OF RESPIRATORY  CANCER  DEATH
       DUE TO A CONTINUOUS EXPOSURE  TO 1  ug/m3  OF  COKE  OVEN EMISSIONS
               UNDER VARIOUS  FORMS OF  THE WEIBULL-TYPE  MODEL
                  WITH APPROXIMATE 95% CONFIDENCE  INTERVAL
Lag Time Total Death Rate
I h(t)
NWM*
0
TOTAL
NWM
5
TOTAL
NWM
10
TOTAL
NWM
15
TOTAL
Risk Due
95% l.b.
1.30x10-8
1.64xlO-8
1.49X10-7
1.99X10-7
6.52x10-7
8.18x10-7
2.00xlO-5
2.65xlO-5
to l ug/m3
Exposure*
m.l ,e.
4.17x10-7
5.47x10-7
2.69x10-6
3.53xlO-6
1.59xlO-5
1.78x10-5
1.52x10-4
1.97xlO-4
Continuous
95% u.b.
8.21x10-6
1.05x10-5
1.63x10-5
2.09x10-5
6.31x10-4
8.41x10-4
8.28x10-4
1. 05xlO-3
                          .

            = nonwhite male.
                                     189

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        TABLE VII-9   LIFETIME PROBABILITY OF RESPIRATORY  CANCER DEATH
        DUE TO A CONTINUOUS EXPOSURE TO 1 ug/m3 OF  COKE  OVEN  EMISSIONS
               UNDER VARIOUS FORMS OF THE MULTISTAGE  TYPE  MODEL
                   WITH APPROXIMATE 95% CONFIDENCE  INTERVAL
Lag Time
I
0
5
10
15
Total Death Rate
h(t)
NWM+
TOTAL
NWM
TOTAL
NWM
TOTAL
NWM .
TOTAL
Risk Due to 1 ug/m3 Continuous
Exposure*
m.l.e. 95%
1.76xlO-6
2.28X10-6
3.57xlO-6
4.67xlO-6
2.81x10-4
3.54X10-4
4.89x10-4
6.29xlO-4
upper bound
2.57x10-4
3.14xlO-4
3.60x10-4
4.45x10-4
6.54x10-4
8.22x10-4
9.76x10-4
1.26xlO-3
        1"NMW = nonwhite male.

COMPOSITE UNIT RISK ESTIMATE
     In Tables VII-8 and VII-9, a variety of unit risk estimates  are  presented
which have been obtained under different models and assumptions.   If  it  is  felt
necessary to obtain a single composite estimate of risk to represent  the maximum
plausible upper bound, the CA6 recommends using the linear upper-bound estimates
of the multistage model.  If low-dose linearity exists, which is  plausible, the
other models would underestimate risk.  The total background U.S. death rate
is used  instead of the  nonwhite male  rate.  The  rationale for this is that the
nonwhite male  rate gives lower estimates because individuals in this group do
not  live as  long on the average, and  thus are  not as  likely to die of cancer.
                                       190

-------
     If it is not known which of the lag-times is most representative of reality,
it is assumed that they are all  equally valid, and the geometric mean of the
four different lag-time estimates is used.
     Using this approach, the composite estimate is calculated to be
            P =sfj/(3.14 x 4~45 x~8.22 x 12.6) x 10~4 = 6.17 x 10"4.

     An alternative approach would be to use the maximum unit risk estimate that
is consistent with the data.  This can be obtained by means of the upper-bound
multistage model, with a 15-year lag-time calculated on the basis of the total
1978 U.S. death rate.  The result would be slightly less than twice  the previous
estimate, or 1.26 x 10-3.

FACTORS THAT HAVE THE POTENTIAL FOR BIASING THE CALCULATED ,ESTIMATED RISKS
     The risk calculations in the previous section were made under the  implicit
assumption that the results were not influenced by additional factors.   However,
many factors undoubtedly did influence the results.  Unfortunately,  not enough
specific information is available about these factors to make it possible to
quantify their influence or even to predict the direction such influence.would
take.  These factors were therefore ignored for the purpose of quantification.
The more important potentially biasing factors are, however, discussed  in this
section in order to provide a subjective feeling for the uncertainties  associated
with the calculated risks and their confidence bounds.
     The reliability of the exposure estimates made for the members  of  the Lloyd-
Redmond cohort are unknown.  These estimates were made  in the 1960s  in  typical
but not identical steel mills not included in the study, and were extrapolated
into the past as far as 60 years.
                                      191

-------
     The LIoyd-Redmond cohort is cross-sectional  in nature in that for an
individual to be a member, he or she had to be employed during the 1951 to
1953 period regardless of age or length of employment.
     The effect of smoking has not been adjusted for due to the unavailability
of sufficiently detailed data.
     The population used to estimate lifetime risk in this analysis consisted of
black males working in physically demanding jobs in which they were exposed to
coke oven emissions over part of their working lifetimes.  The population at
risk due to environmental exposures contains individuals of all sex-race combina-
tions and levels of health, exposed from birth to death.  This raises the
possibility of biases due to susceptible subgroups, such as infants or those
with respiratory diseases.
     The data presented by Mazumdar et al. (1975) suggest that nonwhites and
whites differ in their lung cancer mortality responses for different coke oven
emissions exposures.  At the lowest dose (199 mg/m^-months),  the whites have a
significantly higher lung cancer mortality rate than do nonwhites.  At the
highest dose (>700 mg/m3-months), the opposite is true, since nonwhites have a
significantly (P<0.05) greater lung cancer mortality rate than do whites.  There
is no statistical  difference between the white and nonwhite rates at the two
intermediate doses, 200-499 mg/m3-months and 500-699 mg/m3-months.
     The difference in lung cancer mortality rates between whites and nonwhites
at the highest exposure category may be a  reflection of the open-ended nature
of this category.   Within the 700+ category, Mazumdar et al.  (1975)  reported
that 29 nonwhite and only 2 white workers  were exposed to levels greater than
or equal  to 1200 mg/m^-months of coal  tar  pitch volatiles, which is the
highest exposure level reported.  Obviously, even if most of  the nonwhite
lung cancer deaths had occurred in the 1200+ exposure category, it is

                            ;          192

-------
 unlikely  that  there would  have  been  a  significant  difference  between the white
 and  nonwhite lung  cancer mortality  rates,  since  there were  only two whites  in
 this  category.   Unfortunately,  data  on the lung  cancer mortality  rate at the
 1200+ mg/m3-months exposure was  not  reported  by  Mazumdar et al.   Land  (1976),
 however,  in Table  VII-4, presents data on  the nonwhite lung cancer mortality
 at the exposure  of > 750+ mg/m3-months, which  is  identical to Mazumdar's 900+
 category.  A comparison of the white and nonwhite  rates at this exposure level
 reveals 0/22 respiratory cancer  deaths for whites  and 18/144 for  nonwhites.
 The difference is not statistically significant  at the P < 0.05 level, even
 though exposure  for nonwhites is greater than for  whites within the 900+ group.
 As a  result, there is not much evidence at  this  time that convincingly argues
 that  a real sensitivity difference exists  between  whites and nonwhites.
      The  preferable way of evaluating whether a  white/nonwhite sensitivity
 difference exists would be to obtain the expected  number of cases in the white
 population based on the nonwhite model.  Ideally,  the best data to use for this
 purpose would be data on the vital status  and exposure of each individual  in the
 coke  oven study.   Unfortunately, this data  is not  currently available.
      This analysis has been restricted to the case of cumulative exposure with
 a step-function lag-time adjustment because of the nature of the data currently
 available.  If more data were available,  other models using exposure rate or
 intensity and accounting for lag time differently might  have provided more
 realistic results.
SUMMARY
     Several models have been used to relate cumulative lag-time-adjusted
exposure from coke oven emissions to observed increases in the human respiratory
cancer death rate.  The parameters in the models were estimated using approxi-

                                      193

-------
mate exposure variables and mortality data generated by Lloyd,  Redmond,  and
Mazumdar, and reworked by Land.  The resulting explicit models  were  in turn
used to estimate the lifetime respiratory cancer death risk from a  continuous
exposure to 1 ug/m3 of coal tar pitch volatiles from coke oven  emissions.
     Using the Weibull model, these estimates ranged from 1.30  x 10"8 for  the
95% lower-bound, zero lag-time, and the nonwhite male background death rate
assumption, to 1.05 x 10-3 for the 95% upper-bound, 15-year lag-time, and
total background death rate assumption.  However, these limits  do not allow
for the possibility that the Weibull model does not describe the true dose-
response relationship at low exposure levels.  As a result, even this range  of
5 orders of magnitude does not fully describe the uncertainty associated with
the point estimate.
     To allow for possible model differences, the multistage model  is also
employed to estimate risk.  This model has the advantage of simultaneously taking
into account both parameter estimates and model difference variability.   The 95%
upper limit of this model is based upon finding a polynomial with the largest
linear term that is still consistent with the observed data.  Using this model,
point estimates were obtained for the lifetime risk due to a constant 1  ug/m3
exposure ranging from 1.76 x 10~6 for the zero lag-time case to 6.29 x 10~4
for the 15-year lag-time case.  The 95% upper bounds corresponding to these
extremes range from 2.57 x 10-4 to  1.26 x 1Q-3.  The geometric  mean of the 95%
upper bounds for the four  lag times is calculated to be 6.17 x  10~4, which is
taken to be the composite unit risk estimate.
     It must also be kept  in mind that a  host of additional uncertainties  exists
concerning these estimates.  The effects  of age, sex,  race, general  health,  and
cigarette smoking on the sensitivity of responses to coke oven  emissions are
                                      194

-------
unknown.  The way in which the data were collected and summarized by the
researchers could also introduce additional  biases and uncertainties.   However,
because of the unavailability of sufficient  data to correct for these  factors,
the impact of these factors cannot be addressed in this  assessment.
                                    195

-------
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                                      209
                                                         U.S. GOVERNMENT PRINTING OFFICE 1934 - 759-102/10703

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