United States
Environmental Protection
Agency
Environmental Sciences Research
Laboratory
Research Triangle Park NC 27711
EPA 600 2-80-015
January 1980
Research and Development
Potential
Atmospheric
Carcinogens

Phase  1
Identification and
Classification

-------
                  RESEARCH REPORTING SERIES


 Research reports of the Office of Research and Development, U.S. Environmental
 Protection  Agency, have been grouped  into nine series. These nine broad cate-
 gories were established to facilitate further development and application of en-
 vironmental technology.  Elimination  of traditional  grouping  was consciously
 planned to foster technology  transfer and a maximum interface in related fields.
 The nine series are:

     1. Environmental Health Effects Research

     2. Environmental Protection Technology

     3. Ecological Research

     4. Environmental Monitoring

     5. Socioeconomic  Environmental Studies

     6. Scientific and Technical Assessment Reports (STAR)

     7. Interagency Energy-Environment Research and Development

     8. "Special" Reports

     9. Miscellaneous Reports

 This report has been assigned to the  ENVIRONMENTAL PROTECTION TECH-
 NOLOGY series. This series describes research performed to develop and dem-
 onstrate instrumentation, equipment,  and methodology to repair or prevent en-
 vironmental degradation from point and non-point sources of pollution. This work
 provides the new or improved technology required for the control and treatment
 of pollution sources to  meet environmental quality standards.
This document is available to the public through the National Technical Informa-
tion Service, Springfield, Virginia 22161.

-------
                                          EPA-600/2-80-015
                                          January 1980
       POTENTIAL ATMOSPHERIC  CARCINOGENS
  Phase 1. Identification  and Classification
                     by
         C. R. McMillin, L. B. Mote,
             and D. G. DeAngelis
        Monsanto Research Corporation
             Dayton, Ohio  45407
           Contract No. 68-02-2773
               Project Officer

                 James Mulik
 Atmospheric Chemistry and Physics Division
 Environmental Sciences Research Laboratory
Research Triangle Park, North Carolina   27711
 ENVIRONMENTAL SCIENCES RESEARCH LABORATORY
     OFFICE OF RESEARCH AND DEVELOPMENT
    U.S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NORTH CAROLINA  27711

-------
                           DISCLAIMER
This report has been reviewed by the Environmental Services
Research Laboratory, RTF, U.S. Environmental Protection Agency,
and approved for publication.  Approval does not signify that the
contents necessarily reflect the views and policies of the U.S.
Environmental Protection Agency, nor does mention of trade names
or commercial products constitute endorsement or recommendation
for use.
                                 11

-------
                            ABSTRACT
On the basis of a comprehensive literature search, 20 significant
atmospheric carcinogens were identified from more than 125 high-
volume chemicals having the potential of becoming airborn
pollutants.  The pollutants were divided into probable carcinogens
(substantial data indicating carcinogenicity, generally including
positive animal studies), possible carcinogens (positive mutageni-
city results from at least one fairly well-established test or
from several less established tests), and probable noncarcinogens
(negative results on the bulk of the tests which had been con-
ducted) .   These evaluations are presented along with all of the
references used to make the determinations.

Additional data were collected for the possible and probable
carcinogens including their annual production, emissions, atmo-
spheric persistence, and relative mutagenic and carcinogenic
potencies.  The pollutants were then ranked based on a benzo(a)-
pyrene equivalent (potency) annually emitted remaining after 24
hours in the environment.  From the top portions of these 2
lists, 20 significant carcinogens were chosen for future analysis,
avoiding closely similar chemical types.  A state-of-the-art
review of the effect of cofactors on the carcinogenicity of
chemicals was also completed in the first phase of this research.

To locate optimum sampling sites in cities of interest, a series
of carcinogen isopleths was  generated.  The locations of station-
ary sources of carcinogenic pollutants were first determined.
Using information such as the normalized wind direction and
speed, and the height, temperature, and rate of flow of the
sources,  the probable locations of maximum carcinogenic pollution
concentration were computed.

This report was submitted in partial fulfillment of Contract No.
68-02-2773 by Monsanto Research Corporation under the sponsorship
of the U.S. Environmental Protection Agency.  The report covers
the period 29 September 1977 to 31 October 1978, and work was
completed as of December 1978.
                               111

-------
                            CONTENTS
Abstract	iii
Figures	vi
Tables	vi

   1.  Introduction  	   1
   2.  Conclusions	   3
   3.  Recommendations	   5
   4.  Selection of  20 Significant Atmospheric Carcinogens.  .   6
            Carcinogens selection of candidate chemicals.  .  .   6
            Evaluation of carcinogenicity  	  11
            Summary  report on the review of the carcinogens
              literature	13
            Production of possible and probable carcinogens  .  14
            Emission of possible and probable carcinogens  .  .  14
            Atmospheric persistence of possible and probable
              carcinogens	14
            Potency  of possible and probable carcinogens.  .  .  24
            Relative mutagenic potency	27
            Relative carcinogenic potency  	  27
            Prioritization of possible and probable
              carcinogens	27
   5.  State-of-the-Art Review of Carcinogenic Cofactors.  .  .  32
   6.  Carcinogen  Isopleth Generation 	  33

References	47
Appendices
   A.  Review of the carcinogen literature of 125 chemicals  .  82
   B.  Review of the carcinogen cofactor literature  	 217
                                v

-------
                             FIGURES
Number
   1   Ethylene Bichloride Concentrations in Houston,
         Texas at 500 ug/m3  (3 km/cm)                         31
   2   Input Data                                             32
   3   Output Data                                            36
   4   Houston Carcinogen Isopleth                            40
   5   Locations of Maximum  Concentration of Pollutants
         in Houston                                           41
                             TABLES
   1   Preliminary List of Candidate Carcinogens               3
   2   Sources for Selection of Candidate Chemicals            7
   3   Additional Production Figures                          10
   4   Production-Ranked Probable Carcinogens                 12
   5   Production-Ranked Possible Carcinogens                 13
   6   Emissions-Ranked Probable Carcinogens                  15
   7   Emissions-Ranked Possible Carginogens                  16
   8   Emissions/Persistent-Ranked Probable Carcinogens       17
   9   Emissions/Persistence-Ranked Possible Carcinogens      18
  10   Relative Mutagenic Potency                             20
  11   Preliminary Mutagenic Potency Data                     21
  12   Other Mutagen Data to Consider                         21
  13   Relative Mutagenic/Carcinogenic Potency
         of Probable Carcinogens                              23
  14   Relative Mutagenic/Carcinogenic Potency of
         Possible Carcinogens                                 24
  15   Ranking of Probable Carcinogens by Equivalent
         Emissions of B(a)P After 24 Hours                    25
  16   Ranking of Possible Carcinogens by Equivalent
         Emissions of B(a)P After 24 Hours                    26
  17   Chemicals in Top 30 Probable Carcinogens on MRC
         Data Base That Are Found in Four Cities              29
  18   Average Concentrations at Points of Maximum
         Pollution in Houston                                 40
                                VI

-------
                            SECTION 1

                          INTRODUCTION


The growing recognition that exposure to certain substances in the
environment may pose health hazards has prompted a critical exam-
ination of the available screening procedures and analytical
methodology for reliable monitoring.  Although the U. S. Environ-
mental Protection Agency (EPA) is generally concerned with a wide
range of pollutants, the pollutants or hazardous materials that
are also carcinogenic have been assigned a high priority owing
to their adverse effects on public health.

The objective of this research was to develop sampling and ana-
lytical techniques and instrumentation for 15 of the most signifi-
cant atmospheric carcinogens and field validate the technology
which is developed.  In the first phase of this research several
tasks were completed, including  (1) the identification of 20
significant atmospheric carcinogens from which the EPA was to
select 15 pollutants for study;  (2) the collection of information
pertaining to the effects of cofactors, inhibitors, promoters,
etc., on carcinogens; (3) and the generation of carcinogen iso-
pheths to locate optimum sampling sites in the cities to be used
for field validation of the developed technology.

In order to select these 20 significant atmospheric carcinogens,
Monsanto Research Corporation  (MRC) first selected a number of
candidate chemicals having the potential of becoming atmospheric
pollutants which are produced in fairly high volume and have been
cited in the literature as being carcinogens or portential car-
cinogens.  The primary  (original) literature was consulted to
see whether it indicated that the chemicals were carcinogenic.
The chemicals were then classed as either probable carcinogens,
possible carcinogens, or probable noncarcinogens.  Production
figures, emission figures, environmental persistence data, and
potency data were then assembled in order to prioritize the
chemicals.  Twenty pollutants representing a variety of chemical
types were then selected from the most significant possible and
probable carcinogens.

One complication to the carcinogenic effect of materials considered
in this project is the possible synergistic effects of  other
materials on the chosen carcinogens.  It is well established that
other materials can act as cofactors and either enhance or inhibit

-------
the effects of a known carcinogen.  Often, however, there is not
agreement in the literature as to the precise nature of the syn-
ergistic effects or which materials have this property.  A
comprehensive literature search on the state of the art of car-
cinogenic cofactors therefore was conducted.  This search and the
resulting review concentrated on the effects of various industrial
chemicals on the carcinogenic potential of other industrial chem-
icals.  It also lightly covered other cofactor effects such as
physiological  (e.g., hormonal), genetic, medical  (e.g., disease
states), environmental  (e.g., light), dietary, and other  factors
that affect the initiation or growth of cancers.

A portion of the effort in the first phase of this research was
devoted to determining the location of optimum sampling sites in
four cities where  field validation of the sampling and analysis
equipment and techniques is to occur  (Houston, Los Angeles, Birm-
ingham, and Newark).

In order to accomplish this task,  the MRC Source Assessment Data
Base was used to obtain most  of the necessary input  for the EPA
Climatological Dispersion Model  (COM).  The  chemicals  included in
the study were from the list  of probable  chemical  carcinogens
generated earlier  in the project.  The carcinogenic  isopleths
were generated for Houston for inclusion  in  this report.

During the remaining two years of  this contract, sampling and
analytical techniques and instrumentation will be  developed for
at least 15 of the atmospheric carcinogens  selected  and a field
validation of this methodology will be conducted.

-------
                            SECTION 2

                            CONCLUSIONS


An extensive review of the primary carcinogen and mutagen litera-
ture of more than 125 chemicals having the potential of becoming
atmospheric pollutants was conducted.   It was determined that for
38 of these chemicals there is a substantial amount of informa-
tion confirming either that they are carcinogenic or that they
have been regulated as a carcinogen.  These chemicals usually had
both positive animal studies and mutagenicity tests.  Another 28
chemicals were determined to be possible carcinogens.  For these
chemicals, one or more significant mutagen tests were reported to
be positive but carcinogen results were ambiguous if they had
been conducted.  The remaining chemicals had been labeled poten-
tial carcinogens in this literature at some point.  However, a
careful review of the presently available literature indicates
that they are probably non-carcinogenic.

Information was gathered on the 66 possible and probable carcin-
ogens so that a prioritization model could be used to determine
the most significant atmospheric pollutants.  Production volumes,
emission factors, atmospheric half-life values, mutagenic potency,
and carcinogenic potency were considered in determining the
significance of the pollutants.  A final ranking was made for
both the possible and probable carcinogens based upon the equiva-
lent kilograms of benzo(a)pyrene emitted per year remaining after
24 hours in the atmosphere.

From these two ranked lists, 20 pollutants were selected which
represented a variety of chemical types and were high in the
prioritized ranking.  These chemicals are as follows:  benzo(a)-
pyrene, tetrachloroethylene, ethylene dichloride, benzene, carbon
tetrachloride, ethylene dibromide, toluene-2,4-diamine, dioxane,
acrylonitrile, chrysene, benzyl chloride, benzidine, penta-
chlorophenol, dichloropropene, styrene, hexachlorobutadiene, di-
(2-ethylhexyl) phthalate, vinyl acetate, ethylene oxide, and
acrolein.

A review of more than 2,300 literature citations of  the carcino-
gens cofactor literature was completed.  This review includes
sections on dietary cofactors, physical agents and body materials,
therapeutic agents and treatments, environmental cofactors,
industrial chemicals and pollutants, and esoteric materials  and

-------
other substances.  The development of cancer in laboratory
animals and humans is a complicated process which may be enhanced
or inhibited by a wide variety of conditions.  Probably the most
significant cofactor is smoking.  Smoking exposes individuals not
only to carcinogenic substances but also has been demonstrated to
increase the risk of personnel exposed to agents such as asbestos
and radiation.

A series of isopleths were generated for Houston which  illustrate
that there are three locations in that city with approximately
the same total average carcinogenic pollution burden.   The burden
at the first location is almost totally due to benzene  with a
minor component of ethylene dichloride.  The burden  at  the other
two locations primarily comprise ethylene dichloride with signi-
ficant amounts of carbon tetrachloride and chloroform and lesser
amounts of trichloroethylene  and vinyl chloride.  A model of the
isopleths illustrates the importance of properly selecting the
sampling sites.

-------
                            SECTION 3

                          RECOMMENDATIONS


It is recommended that 15 chemicals be selected by EPA for use in
this research from among the 20 chemicals listed in the Con-
clusions section.  These chemicals will be the target pollutants
for the research on sampler development and analytical technique
development.  With the prioritization model devised for this
research, the relative significance of any other chemicals or
pollutants of interest can easily be determined.

A large number of varied influences affect the development of
cancer in humans and animals.  With the exception of smoking,
which is clearly an important carcinogenic cofactor, the signi-
ficance of many of these cofactors has yet to be demonstrated.

From the carcinogen isopleths generated for Houston, it is readily
apparent that the sampling location selected greatly influences
the quantity and composition of the pollutants being monitored.
Since a greater variety of pollutants can be found at the second
and third of the three locations examined, it is recommended that
one of these locations be used for the field validation of the
sampler for this contract and for contract 68-02-2774, using the
portable carcinogen sampler.

-------
                            SECTION 4

       SELECTION OF 20 SIGNIFICANT ATMOSPHERIC CARCINOGENS


The first task required in this contract was to identify 20
significant atmospheric, carcinogenic, pollutant chemicals.  In
order to select these 20 significant atmospheric carcinogenics,
Monsanto Research Corporation  (MRC) first selected a number of
candidate chemicals which are produced in fairly high volume and
have been cited as being a carcinogen or potential carcinogen by
some piece of literature.  The primary  (original) literature was
consulted to see whether it indicated that the chemicals were
carcinogenic.  The chemicals were  then classed as either probable
carcinogens, possible carcinogens, or probable noncarcinogens.
Production figures, emission figures, environmental persistence
data, and potency data were then assembled in order to  prioritize
the chemicals.  Twenty chemicals representing a variety of chem-
ical types were then  selected  from the most  significant possible
and probable carcinogens.

SELECTION OF CANDIDATE CHEMICALS

The first list of candidate chemicals was obtained by determining
which chemicals on the MRC Source  Assessment Data Base  [1] are
also found on the 1976 NIOSH Suspected Carcinogen List  [2].
 [1] Eimutis, I. C.,  and  R.  P.  Quill.   Source  Assessment:   Non-
    criteria Pollutant Emissions.   EPA-600/2-77-107e  (National
    Technical  Information  Service  No.  FB  270  550),  1977.

 [2] Suspected  Carcinogens  - A  Subfile  of  the  NIOSH  Toxic  Sub-
    stances List, 1976 Edition, H.  E.  Christensen,  ed.  Publi-
    cation No.  (NIOSK) 75-188, U.S. Department of Health,
    Education, and Welfare, National Institute for  Occupational
    Safety and Health.

-------
It was determined that 83 compounds on the MRC emissions data
base were also on the 1976 NIOSH Suspected Carcinogen List or
were cited in the "Registry of Toxic Effects of Chemical Sub-
stances"  [3] as a mutagen, teratogen, or neoplastic agent.  Of
these 83, 47 compounds had references indicating positive muta-
genic, carcinogenic, teratogenic, or neoplastic test results.
The remaining 36 are on the suspected carcinogen list only be-
cause of current interest, with citations such as "currently
undergoing tests,"  "candidate for additional oncological infor-
mation," or "EPA selected for priority attention as point source
water effluent discharge toxic pollutant."  These two lists of
chemicals are shown in Table 1.

Dr. Sawicki's  list  of  atmospheric vapors  and  gases [4]  was checked
against the NIOSH list, and materials common to both compilations
were found to be present on our list.  The 1972-1973 "Survey of
Compounds Which Have Been Tested for Carcinogenic Activity" [5]
for which positive  results were obtained was checked against the
source assessment data base.  It was found that our preliminary
list included all compounds common to both tabulations.

A  report entitled "Preliminary Scoring of Organic Air Pollutants"
lists 637 organic chemicals along with their production, volatil-
ity, and toxicity data  [6].  Of these chemicals, 108 are cited as
being either mutagenic or carcinogenic, or as producing neoplasms,
Subtracting the chemicals already under consideration and the
high polymers reduced the number to 74 materials.  Eliminating
chemicals for which production figures were not available or were
less than 455,000 kilograms  (1 million pounds) per year produced
a  list of 20 chemicals to be further evaluated.  There are listed
below with their annual production.
 [3] Registry of Toxic Effects of Chemical Substances, Volumes I
    and  II, E. J. Fairchild, ed.  DHEW Publication No.  (NIOSH)
    78-104-A, U.S. Department of Health, Education, and Welfare,
    National Institute for Occupational Safety and Health,
    September 1977.

 [4] Sawicki, E.  Chemical Composition and Potential "Genotoxic"
    Aspects of Polluted Atmospheres.  In:  Air Pollution and
    Cancer in Man, U. Mohr, D. Schmahl, and L. Tomatis, eds.
    International Agency for Research on Cancer Scientific  Pub-
    lication No. 16, 1977.  pp. 127-157.

 [5] Survey of Compounds Which Have Been Tested for Carcinogenic
    Activity, Volumes 1 through 7.  DHEW Publication No.  (NIH)
    75,  Public Health Service Publication No. 149, U.S. Depart-
    ment of Health, Education, and Welfare, National Institutes
    of Health.

 [6] Fuller, B., et al.  Preliminary Scoring of Selected Organic
    Air  Pollutants.  National Technical Information Service Nos.
    PB 264 442 through PB 264 446, 1976.

-------
TABLE 1.  PRELIMINARY LIST OF CANDIDATE  CARCINOGENS

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
Carcinogenic/neoplastic/
teratogenic/mutagenic
compounds
Trichloroethylene
Vinyl chloride
Benzene
Formaldehyde
Maleic anhydride
Carbon tetrachloride
Chloroprene
Methyl ethyl ketone
Ethylene oxide
Propylene oxide
Phenol
1 , 1-Dichloroethane
Chloroform
Naphthoquinone
Ethylene dibromide
Dichlorobutene
Benzo (a) pyrene
Methyl methacrylate
Acrylonitrile
Epichlorohydrin
Hydroquinone
Biphenyl
Naphthalene
Propanol
Parathion
Chloracetic acid
Dichlorophenol
Methylenedianiline
Benzyl chloride
DDT
Polychlorinated biphenyls
Naphthyl methylcarbamate
Quinone
Hydrazine
Endosulfan
Dichloronaphthoquinone
Trichlorophenol
Methylstyrene
Dichlorovinyl dimethyl phosphate
Trichlorfon
Anthracene
Benz (a) anthracene
Bis (chloromethyl) ether
Captan
Diazinon
Nitrosodimethylamine
Pyrene
Emissions ,
metric No. of industry
tons/yr types emitting^
158,070
142,290
102,348
40,695
18,764
12,672
7,459
5,324
4,540
4,386
4,383
2,559
1,069
1,051
886
866
830
727
538
224
101
92
90
5
42
37
37
26
24
19
18
12
6
3
2
0
0
0
0
0
0
<0
<0
<0
<0
<0
<0



































.9
.5
.5
.2
.1
.1
.1
.1
.1
.1
.1
.1
5
6
15
16
3
11
2
2
8
2
13
2
4
1
2
1
58
1
4
2
1
1
1
2
1
3
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
                                              (continued)

-------
TABLE 1  (continued)



1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Candidates with no
references cited
Toluene
Trichloroe thane
Tetrachloroethylene
Ethylene dichloride
Acetone
Methylene chloride
Carbon disulfide
Methyl chloride
Ethanol
Acrolein
Styrene
Vinylidene chloride
Dichlorodif luoromethane
Allyl chloride
Dichloroethylene
Trichlorof luoromethane
Aniline
Nitrobenzene
Nitrophenols
Heptachlor
Malathion
Tetrachloroe thane
Diphenyl oxide
Methyl bromide
o-Dichlorobenzene
p-Dichlorobenzene
Kelthane
Endrin
Dinitrotoluene
Nitrochlorobenzene
Dichloropropionic acid
Dursban
Ethyl benzene
Fluoranthene
Guthion
Toxaphene
Emissions
metric No. of industry
tons/yr types emitting
331,473
180,128
77,418
67,079
29,057
27,138
25,768
22,944
11,548
6,495
5,625
1,328
425
421
419
85
8
45
11
11
10
9
7
6
3
3
2
2
0.4
0.3
0.2
0.1
0.1
<0.1
<0.1
<0.1
11
1
4
10
11
5
7
7
12
4
4
4
1
2
1
1
3
3
1
1
1
1
2
1
2
2
1
1
1
1
1
1
1
1
1
1

-------
                                              Production,
        	   Chemical	        kg/yr

       Acetaldehyde                               680
       Aldrin                                      11
       Benzidine                                    5
       Chlorobenzilate                              1
       Cumene hydroperoxide                       900
       Di-(2-ethylhexyl) phthalate                180
       Dimethylhydrazine                            0.5
       Disodium methanearsonate                    16
       Eptam                                        2
       Ethylene glycol                          1,700
       Ethylenimine                                 2
       Hexamethylenetetramine                      46
       4,4'-Methylene bis (2-chloroaniline)          3.5
       Morpholine                                  10
       Naphtha                                  3,800
       Pentachlorophenol                           20
       n-Pentane                                  220
       Sorbic acid                                 18
       Tetraethyl lead                            160
       Toluene-2,4-diamine                         29

Of the 80 compounds covered in the report,  "Research  Program on
Hazard Priority Ranking of Manufactured Chemicals" [7], 33 had
already been considered.  Excluding solids  such as polyurethane,
high-boiling liquids  such as silicone  fluids, and low-volume
chemicals such as vat blue dye #6 left 16 chemicals to be con-
sidered for this project.  Three of them  (perchloroethylene,
vinyltoluene, and 2-mercaptothiazole) were  tentatively identified
as being noncarcinogens.  A fourth, bis (2-chloroethyl) ether, is
produced or released  in extremely small quantities, if at all.
The remaining 12 are  as follows:

       Hexachlorobenzene
       Hexachlorobutadine
       Tetrabromoethane
       Dichloropropene
       Sulfolane
       2-Methoxyethanol
       4,4-Methylene bis(2-chloroaniline)
       Dimethylamine
       Dioxane
       Ethylenimine
       Benzidine
       Dichlorobenzidine
[7] Brown, S. L., et al.  Research Program on Hazard Priority
    Ranking of Manufactured Chemicals.  National Technical
    Information Service No. PB 263 161, 1975.


                               10

-------
"Review of the Environmental Fate of Selected Chemicals"
evaluates 74 suspected carcinogens for their environmental per-
sistence.  More than 20 of these chemicals were already under
consideration.  Many of the rest of the chemicals are either
produced in low quantities  (<455 kg/yr) or are essentially non-
volatile.  The remaining chemicals and their production volumes
are listed below:

       Di-tert-butyl
         peroxide         1.4 x 106
       Hydrogen peroxide  0.9 x 106  Normal metabolite
       1-Naphthylamine    3.2 x 106
       Benzoyl chloride   6.8 x 106  Air 1/2 life = 10 min

A series of reports on 11 compounds prepared by the Office of
Air Quality Planning and Standards Department of EPA consists of
carcinogenic and mutagenic information for the air pollution
assessment of these compounds.  Those which were not yet being
considered were added to our list.

MRC's Environmental Analytical Sciences Center (EASC) personnel
suggested that a few other high-volume chemicals should be con-
sidered  in this project if they are reported to be carcinogens
or mutagens, including:

       Chloropropane
       Dimethyl acetamide
       Vinyl acetate
       Vinyl bromide

A summary of the sources of candidate chemicals for investigation
in this  project is shown in Table 2.

EVALUATION OF CARCINOGENICITY

An attempt was made to obtain primary literature references for
each of  the chemicals under consideration.  A computer informa-
tion retrieval search was also made for each of the chemicals
using both the CANCERLINE and TOXLINE data bases.  The primary
literature shows on what basis a chemical was added to the NIOSH
Suspected Carcinogen List while the CANCERLINE and TOXLINE bases
list recent tests run on the compounds and current thoughts on
each compound in the published literature.

Based on these sources of data, coupled with information from
Reference 5, a qualitative determination was made as to which
chemicals are probable carcinogens, possible carcinogens, or
probable noncarcinogens for purposes of this project.

Many of  these chemicals are currently undergoing carcinogenicity
tests.   Therefore, these lists represent only an indication of
which chemicals will probably be labeled as carcinogens after


                               11

-------
     TABLE  2.   SOURCES FOR SELECTION OF CANDIDATE  CHEMICALS
     Number of
     potential
     candidates
Number of
candidates
 selected
              Source
         >300
          637
           80
           74




           11

           >4
       XL,106
    83
    20
    12
     4

     4
   127
MRC  Source Assessment Data Base  [1]  and
  NIOSH Suspected Carcinogens List [2]

Preliminary Scoring of Organic Air
  Pollutants [6] and indicated as a
  carginogen or mutagen

Research Program on Hazard Priority
  Ranking of Manufactured Chemicals [7]
  and indicated as a mutagen or
  carcinogen

Review of the Environmental Fate of
  Selected Chemicals [8] and production
  of >455 kg/yr

Miscellaneous sources

Suggested by EASC
comprehensive testing  is complete.  The  inclusion of chemicals
with  so  little data  is necessary for  this  project since only a
few chemicals have been specifically  designated as known human
carcinogens.

In the evaluation of carcinogenicity,  two  of the major problems
encountered were lack  of data and conflicting data.  Maleic
anhydride exemplifies  the former problem.   It is on the NIOSH
list  because of a 1961 test where two  out  of three male rats of
an unspecified strain  developed local  sarcomas after repeated
injections of maleic anhydride.  A check of the current litera-
ture  did not uncover any other significant tests which have been
conducted on maleic  anhydride.

Conflicting data exist for formaldehyde.   Many reports show for-
maldehyde as  a mutagen and/or a carcinogen in many types of
short-term test systems.   There are also comments to the effect
  !] Radding,  S.  B., et al.   Review of the Environmental Fate of
    Selected  Chemicals.  EPA-560/5-77-003  (National Technical
    Information  Service No.  PB 267 121), May  1977.
                                  12

-------
that humans have repair mechanisms for the damage done by for-
maldehyde.  We therefore decided to consider formaldehyde a
possible carcinogen.

Another problem is that some of the suspected carcinogens have
been administered with benzene as the solvent.  The solution was
to disregard such data if there were sufficient other data avail-
able on the compound.  If other data were not available, we had
to consider whether benzene was carcinogenic by the route of
administration, and as a last resort, how potent benzene was by
that route of administration.

In addition to the available primary references, general sources
of information on the carcinogenicity of chemicals were consulted,
such as International Agency for Research on Cancer Monographs
and results from National Cancer Institute bioassays.

In the search for information on 127 fairly high-volume chemicals
suggested by some type of literature as being carcinogenic, sub-
stantiating carcinogenic data were found in the literature for
38.  These were labeled probable carcinogens.   Information such
as mutagenicity data indicated that another 28  chemicals may
possibly be carcinogenic, although data on them are incomplete.
These 28 were labeled possible carcinogens.

This project has as its ultimate product an ambient air sampler
coupled with an analytical protocol capable of  sampling a broad
range of chemicals.  As such, the evaluation of what is a possi-
ble carcinogen has been fairly broad  (e.g., one positive estab-
lished mutagenic test), and chemicals on the resulting list
should not be construed as requiring regulation, but only as
chemicals in which there are positive mutagenic indicators.  In
general, however, more data are needed.

SUMMARY REPORT ON THE REVIEW OF THE CARCINOGEN LITERATURE

A summary report has been generated which reviews the available
carcinogen literature on more than 125 chemicals.  Based on
abstracts of the primary literature, and the actual papers where
possible, a determination was made in each case as to how the
chemical would be classified for this report.

Chemicals for which the overwhelming preponderance of information
indicated carcinogenicity or for which regulations had already
been enacted to treat the chemical as a carcinogen  (e.g., benzene)
were classed as probable carcinogens.  This generally included
positive animal studies coupled with positive mutagenicity tests.

Chemicals on which one or more significant mutagenicity tests
were positive  (a positive result in at least one well-established
mutagen test) with ambiguous carcinogen results were labeled
                                13

-------
 possible carcinogens.   It is believed that if enough animal
 species and routes of  administration were tested,  these chemicals
 would most likely be labeled carcinogenic.

 The remaining chemicals have been labeled potential carcinogens
 at some point in the literature.   However, a careful review of
 the presently available literature indicates that they are
 probable noncarcinogens.

 For the 66 probable and possible carcinogens, more data were
 obtained pertaining to quantity emitted, quantity produced, some
 market forecasts, persistence in the air  (primarily as related
 to photo-oxidation and reaction with HO and O3 radicals), and
 measures of volatility (boiling point and vapor pressure).

 A cumulative listing of the summaries of the 125 chemicals  eval-
 uated containing the above information along with all of the
 references to where the information was obtained is included as
 Appendix A.

 PRODUCTION OF POSSIBLE AND PROBABLE CARCINOGENS

 In addition to the production figures cited in Appendix A,  "A
 Review of the Carcinogen Literature of 125 Chemicals," production
 information was gleaned from Chemical and Engineering News,
 Chemical Marketing Reporter, and from a multiclient research
 service to which we subscribe.  A summary of these additional
 production volumes is  shown in Table 3.

 Using data from the above sources, the probable and possible
 carcinogens were ranked according to production volume, as  shown
 in Tables 4 and 5.  The most recent production data were consid-
 ered most significant.

EMISSION OF POSSIBLE AND  PROBABLE  CARCINOGENS

 Although the ranking of the chemicals in Tables 4  and 5 indicates
 which materials should be considered "high-volume" chemicals,  a
 more realistic approach to ambient air sampling should depend on
 the amount of the chemical being released to the atmosphere.
 Thus the emissions will be the basis for all future ranking of
 these chemicals.   The  production  figures obtained  were utilized
 to  calculate  the  quantity emitted in cases where literature
 values  for emissions were not available.

 The  starting  point for each of the chemicals was its quantity
 emitted.   Where this information  was  not  available, a  simplified
 assumption was  made along the  lines  of  Fuller,  et al.  [6, PB  264
 442], that a  fraction  (e.g.,  0.015)  of  production is lost to the
 atmosphere, to  determine  the quantity emitted per year.
                               14

-------
TABLE 3.  ADDITIONAL  PRODUCTION FIGURES'

Chemical
Acrolein
Acrylonitrile

Aldrin
Allyl chloride"
Benzene

Benzyl chloride

Biphenyl
Captan
Carbon tetrachloride


Chlordane
Chloroform
Chloroprenec
Dichlorobutene
Dichloropropene
Dichlorovinyl dimethyl
phosphate
Di- (2-ethylhexyl) phthalate
Dinitro toluene^
Epichlorohydrin
Ethylene dibromide
Ethylene dichloride


Ethylene oxide

Formaldehyde


Heptachlor
Hexachlorobenzene
Mercaptobenzothiazole
Methyl chloride
Methylenediamine^
Morpholine
1-Naphthylamine
Nitrochlorobenzene"1

Pentachlorophenol

Propylene oxide

Styrene


Tetrachloroethylene

Tetraethyl lead
Tetraethyl lead and
tetramethyl lead
Toluene-2 , 4-diamine
Trichloroethylene
Trichlorophenol ]
Production,
kg
6.1 x 10s
6.8 x 108
6.4 x 108
3.0 x 10s
2.1 x 10s
6.4 x 108
4.8 x 109
4.1 x 107
4.1 x 107
2.2 x 107
4.5 x 106
3.5 x 10s
4.9 x 108
4.7 x 10s
9.6 x 106
1.5 x 108
1.4 x 108
1.4 x 10s
2.5 x 107

3.2 x 106
1.8 x 108
1.0 x 108
8.2 x 107
1.5 x 108
5.5 x 109
4.5 x 109
4.2 x 109
2.0 x 109
1.9 x 109
2.9 x 109
2.5 x 109
2.9 x 109
9.1 x 10s
4.5 x 10s
2.8 x 106
1.x x 108
1.6 x 108
1.1 x 107
decreasing
6.2 x 107
4.7 x 107
1.8 x 107
2.2 x 107
7.7 x 108
7.3 x 108
3.0 x 109
2.1 x 109
2.7 x 109
3.3 x 108
3.3 x 108
1.6 x 108

3.0 x 108
1.0 x 10s
1.6 x 10s

Year
1974
1976
1974
1974
1975
1976
1973
1976
1974
1975
1975
1978
1975
1974
1974
1976
1976
1976
1976

1976
1974
1976
1973
1973
1977
1974
1973
1975
1974
1978
1976
1973
1974
1974
1974
1976
(1976)
1974

1976
1973
1975
1973
1976
1975
1977
1975
1973
1976
1974
1973

1976
1976
1975

Production,
kg

5.5 x 108
6.3 x 10


5.0 x 109

3.2 x 107



3.7 x 108
4.1 x 10s
4.8 x 108

1.3 x 108








5.5 x 109
3.5 x 109

1.7 x 109
1.9 x 109
2.8 x 109
2.7 x 109




1.4 x 10e

1.1 x 107

4.9 x 107

2.3 x 107

6.8 x 108
7.9 x 108
2.9 x 109
2.7 x 109

3.2 x 108
3.2 x 10e


3.1 x 108

2.0 x 10s

Year

1975
1973


1974

1975



1977
1975
1973

1975








1976
1974

1975
1973
1977
,1974




1975

1973

1974

1974

1975
1974
1976
1974

1975
1973


1975

1974

                                   (continued)
                   15

-------
                     TABLE  3   (continued]
Chemical
Vinyl acetate

Vinyl bromideJ
Vinyl chloride

Vinylidene chloride
Chrysene K
Production,
kg
4.
1.
1.
2.
2.
7.
1.
8
0
9
6
5
0
7
X
X
X
X
X
X
X
10s
108
105
109
109
107
10"
Year
1975
1974
1975
1976
1974
1976
1977
Production,
kg
6.4
6.8

1.8
2.4


x 10s
x 10B

x 109
x 109


Year
1974
1973

1975
1973


 Production figures cited are derived from the following sources,
 with no more than two years of figures per reference:   Chemical
 and Engineering News, June, 1975;  Chemical Marketing Reporter,
 various issues; and a multiclient  research service subscription
 (complete information is not available to the general public).
 Capacity.

 The 1976 production of polychloroprene was 1.4 x 10a kg.  Assume
 1.4 x 10s kg of chloroprene was produced for this use.

 Butadiene is converted to either 2,3-dichlorobutene-l for
 chloroprene manufacture of 1,4-dichlorobutene-2 for adiponitrile
 manufacture.  In 1976, 1.4 x 108 kg polychloroprene was produced.
 Assume 1.4 x 10s dichlorobutene may have been used.

 The Dow capacity for dichloropropene was 14 million kilograms
 in 1976 while the Shell capacity for a dichloropropene/
 dichloropropane mixture was 22 million kilograms.  Assume half
 the Shell mixture was dichloropropene and the capacity equals
 the production to give 2.5 x 10s kg for both facilities.

 Dinitrotoluene is an intermediate in the manufacture of toluene
 diamine.  A gross assumption would be to equate the production
 of these chemicals.

^6.6 x 10s kg formaldehyde was used to make methylenedianiline,
 with 0.41 kg formaldehyde used for each kg of methylenedianiline
 produced.  This yields a production of 1.6 x 108 kg
 methylenedianiline.

 In 1976, 2.4 x 107 kg of HNO3 were used to make nitrochloro-
 benzene where 0.42 kg HNO3 is used to make 1.0 kg nitrochloro-
 benzene.  Therefore, the 1976 production of nitrochlorobenzene
 was about 6.2 x 107 kg.

 The use of 2,4,5-T herbicide has been restricted by the
 government.
 To produce SEF® modacrylic, 9% vinyl bromide is used.   Assume
 25% of the 1.14 x 107 kg modacrylic capacity was SEF and it was
 operating at 68% capacity to give  a vinyl bromide consumption
 of 1.9 x 105 kg.
1^
 Assume 150 mg chrysene per gram organic atomospheric particulate
 matter.   MRC Source Assessment Data Base, July 1977, cites
 1.13 x 108 kg of benzene soluble organic particulate matter
 emitted from stationary sources.  This reduces to 1.7  x 10" kg
 chrysene emitted (and produced).
                                16

-------
 TABLE 4.   PRODUCTION-RANKED PROBABLE CARCINOGENS

Rank
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37

38
Chemical
Ethylene dichloride
Vinyl chloride
Acrylonitrile
Benzene
Carbon tetrachloride
Tetrachloroethylene
Chloroform
Trichloroethylene
Dichlorobutene
Epichlorohydrin
Ethylene dibromide
Toluenediamine
Dinitrotoluene
Vinylidene chloride
Benyl chloride
DDT
Hydrazine
Chlordane
Dioxane
Benzidene
Captan
Methylene bis (chloroaniline)
Ethylenimine
Dichlorobenzidine
Heptachlor
Chlorobenzilate
Benzo (a)pyrene
Dimethy Ihydraz ine
Chrysene
Diaminanisole
Benz (a) anthracene
Tetrachloroe thane
Bis (chloromethyl) ether
Nitrosodimethylamine
Ethyl carbamate (urethane)
Trichlorof on
Polychlorinated biphenyls
(1.8 x 107)
Aldrin (3.0 x 106)
Production,
kg
5.5 x 109
2.6 x 109
6.8 x 10s
6.4 x 108
3.8 x 108
3.2 x 108
1.5 x 108
1.4 x 108
1.4 x 108
1.4 x 108
1.2 x 108
1.0 x 10s
1.0 x 10B
7.0 x 107
4.1 x 107
2.0 x 107
1.7 x 107
9.6 x 106
7.4 x 106
4.7 x 106
4.5 x 106
3.5 x 106
2.2 x 106
2.1 x 106
9.1 x 105
9.0 x 105
8.3 x 105
<5.0 x 105
1.7 x 10*
1.4 x 10*
1.0 x 10*
9.4 x 103
<4.5 x 102
<4.5 x 102
<4.5 x 102
1.0 x 102

-0-
-0-
Year
1977
1976
1976
1976
1977
1976
1976
1976
1976
1973a
1975
1976
1976b
1976
1976
1971
1974
1974
1973
1976C
1975
1972
1974
1976C
1974
1976C
1977c,d
1973
1977d
1978C,e
1977c'f
1977c,d
1974
1977C
1974C
I977c ,d

19749
19749

 Average of several different numbers.
 Intermediate in toluene diamine manufacture.   Assumed
 equal production.
 Document published in cited year which contains  production
 figure.
 Assume emitted quantity equals produced quantity.
 Quantity imported.
 Assume emission is 1% of production from stationary sources
 and ignore nonstationary sources.
^Current production assumed to be zero, but literature
 values also cited.
                             17

-------
         TABLE 5.   PRODUCTION-RANKED POSSIBLE CARCINOGENS
    Rank
Chemical
Production,
    JSSL
Year
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19

20
21
22
23
24
25
26
27
28
Styrene
Formaldehyde
Ethylene oxide
Cumene hydroperoxide
Propylene oxide
Vinyl acetate
Allyl chloride
Di- (2-ethylhexyl) phthalate
Methyl chloride
Tetraethyl lead
Chloroprene
Nitrochlorobenzene
Pentachlorophenol
Dichloropropene
Acrolein
Me thy lenedi aniline
Morpholine
Hexach lore-butadiene
Dichlorovinyl dimethyl
phosphate
1-Naphthylamine
Mercaptobenzothiazole
1 , 1-Dichloroethane
Di-tert-butyl peroxide
Hexach lor obenzene
Vinyl bromide
Dichloronaphthoquinone
Trichlorophenol
Biphenyl (2.2 x 107)
3
2
2
1
7
4
2
1
1
1
1
4
2
2
1
1
1
8

3
3
2
2
1
4
1
9
5

.0
.1
.0
.4
.7
.8
.1
.8
.7
.6
.6
.9
.1
.8
.4
.3
.1
.0

.2
.2
.8
.6
.4
.5
.9
.0
.0

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

X
X
X
X
X
X
X
X
X
-fl-
lC
10
10
10
10
10
10
10
10
10
10
10
10
9
9
9
9
8
8
8
8
8
8
8
7
7
107
10
10
10
10

10
10
10
10
10
10
10
7
7
7
6

6
6
6
6
6
5
5
102
10

2.

1977
1975
1975
1974
1976
1975
1975
1974
1976
1973
1974
1974
1975a
1976
1974a
72, 76
1974
1975b

1976
1974
1974
1977b '
1977b
1974
1975d
1977b>
1977b'
1975e













a






c



c
c


     Average  of  production figures.

     Date  of  publication of reference.

     Assume emissions  are equal  to production.

     Rough estimate.
    e
     Current  production  is assumed to be  zero since  the pro-
     duction  of  polychlorinated  biphenyls  (PCB's) has stopped.
     Literature  value  is  given for comparison.

In cases where this type  of  calculation was needed, the nature of
the chemical  involved  was  considered.  A fraction such as 0.01
was assumed for  chemicals  which  are used as intermediates for
other chemicals  or in  other  nondispersive manners, while the
fraction 1.00 was used when  it was assumed that all of the
                                18

-------
chemical produced is deliberately released to the environment.
(In one case, 1.03 was used; it represents 100% of production
plus a 3% fugitive emission from production sources.)  Much more
weight has been placed on figures from the literature which have
been more extensively evaluated than on those numbers where an
emission factor had been used to calculate emissions.  Where no
other values were available, emissions were assumed to be a
fraction of production as related above.  The emissions-ranked
probable and possible carcinogens are shown in Tables 6 and 7.

Where more than one significant emission figure was available,
the log average was used, with the MRC Source Assessment Data
Base emissions given twice the weight of other information.

ATMOSPHERIC PERSISTENCE OF POSSIBLE AND PROBABLE CARCINOGENS

In this project, atmospheric carcinogens are of interest as
opposed to occupational carcinogens.  For carcinogens to be pre-
sent in the atmosphere, they need to have some stability.  A few
of the carcinogens are rapidly degraded by light, moisture, or
other factors as opposed to a few other that are known to have a
very long environmental persistence.  It seems reasonable that
carcinogenic chemicals that degrade in moments in the atmosphere
should be considered less significant than those that are very
persistent in the environment.

Several time frames were considered to determine how environ-
mental persistence should be regarded as a factor in the
concentration of carcinogens in the atmosphere.  A long time
frame  (e.g., 30 days) would allow for the disappearance of those
materials that degrade as they move away from the source.  How-
ever, many of the sources of emissions are located near cities in
which the population would be exposed in a matter of a few hours.
Twenty-four hours was chosen as a reasonable time.

The literature references used for this calculation are shown in
Appendix I in the summaries of each of the chemicals.  The half-
life used was that quoted for photodegradation, HO radical, and
03 radical reactions with the test chemicals.  Tables 8 and 9
show the annual quantities of probable and possible carcinogens
emitted that would be in the atmosphere 24 hours after emission.

If no data were available on degradation, it was assumed that the
quantity emitted remained after 24 hours.  In general, this per-
sistence correction factor was only significant for the few
chemicals indicated in the literature to have atmospheric half-
lives of minutes to hours.
                                19

-------
TABLE 6
EMISSIONS-RANKED  PROBABLE CARCINOGENS
    Rank
         Chemical
Emissions,
  kg/yr
      1    Trichloroethylene               1.7
      2    Tetrachloroethylene              1.2
      3    Vinyl chloride                  1.2
      4    Ethylene dichloride              9.8
      5    Benzene                         7.4
      6    Chlordaneb                      9.6
      7    Dioxaneb                        7.4
      8    Ethylene dibromide              4.8
      9    Chloroform                      2.6
     10    Carbon tetrachloride             1.6
     11    Chlorobenzilateb                9.0
     12    Dichlorobutene                  8.7
     13    Benzo(a)pyreneb                 8.3
     14    Toluene-2,4-diamine              4.4
     15    Vinylidene chloride              4.1
     16    Benzyl chloride0                4.1
     17    Acrylonitrile                   3.7
     18    Epichlorohydrin                 2.2
     19    Benzidine                       7.0
     20    Methylene bis (chloroaniline)     4.5
     21    Ethylenimine                    2.7
     22    DDTd                             1.9
     23    Chrysene                        1.7
     24    Heptachlor                      l.l
     25    Tetrachloroethane^              9.4
     26    Dimethylhydrazinec             <5.0
     27    Dichlorobenzidine               4.5
     28    Hydrazine                       3.5
     29    Dinitrotoluene                  4.0
     30    Diaminoanisolec                 1.4
     31    Trichlorfon                     1.0
     32    Benz(a)anthracene0             <1.0
     33    Bis(chloromethyl)  ether        <1.0
     34    Captan                         <1.0
     35    Nitrosodimethylamine            <1.0
     36    Ethyl carbamate (urethane)c      4.5
     37    Aldrin (3.0 x 106)b,e            Q
     38    Polychlorinated biphenyls
             (1.8 x 105)C,e                o
                                   x 108
                                   x 108
                                   x 108
                                   x 107
                                   x 107
                                   x 106
                                   x 106
                                   x 106
                                   x 106
                                   x 107
                                   x 105
                                   x 105
                                   x 105
                                   x 10s
                                   x 105
                                   x 105
                                   x 105
                                   x 105
                                   x 10*
                                   x 10*
                                   x 10*
                                   x 10*
                                   x 10*
                                   x 10*
                                   x 103
                                   x 103
                                   x 103
                                   x 103
                                   x 102
                                   x 102
                                   x 102
                                   x 102
                                   x 102
                                   x 102
                                   x 102
    When more  than  one  significant  emission  figure
    is available, the log  average is  used, with  the
    MRC data base figure given  twice  the weight  of
    the other  values.

    Assumed emission factor of  1.00 of  production.

    Assumed emission factor of  0.01 of  production.

    Emitted from stationary sources  (MRC Source
    Assessment Data Base,  July  1977).
    a
    "Current production  (emission) of  zero, but
    average literature values also given.
                        20

-------
TABLE 7.  EMISSIONS-RANKED POSSIBLE CARCINOGENS
                                      Emissions,
Rank             Chemical               kg/yr
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27

28
Formaldehyde
Dichloropropeneb
Pentachlorophenol'-1
Cumene hydroperoxide
Methyl chloride
Ethylene oxide
Hexachlorobutadine
Chloroprene
Tetraethyl lead
Acrolein
Styrene
Morpholine
Propylene oxide
1 , 1-Dichloroethane
Di- (2-ethylhexyl) phthalate
Allyl chloride
Vinyl acetate
Hexachlorobenzene
l-Naphthylaminec
Mercaptobenzothiazole
Methylenedianiline
Di-tert-butyl peroxide0
Vinyl bromide
Dichloronaphthoquinone
Trichlorophenol
Nitrochlorobenzene
Dichlorovinyl dimethyl
phosphate
Biphenyl (9.2 x I0^)d
4.8 x 107
2.8 x 107
2.1 x 107
2.1 x 107
1.6 x 107
9.7 x 106
7.3 x 106
6.9 x 106
6.6 x 106
6.5 x 106
5.6 x 106
5.5 x 106
4.4 x 106
2.6 x 106
2.4 x 106
7.1 x 105
6.8 x 105
2.3 x 105
3.2 x 10*
2.7 x 10"
2.6 x 10"
1.4 x 104
4.0 x 103
9.0 x 102
5.0 x 102
3.0 x 102

2.0 x 102
0

 When more than one significant emission figure
 is available, the log average is used, with the
 MRC data base figure given twice the weight of
 the other values.
 Assumed a release factor of 1.00 of production.

 Assumed a release factor of 0.01 of production.

 Current production of PCB's is zero, so assumed
 biphenyl emissions also zero.  Literature value
 is also given.
                      21

-------
TABLE 8.   EMISSIONS/PERSISTENT-RANKED PROBABLE  CARCINOGENS
Rank
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38

Atmospheric
Chemical half-life
Ethylene dichloride
Tetrachloroethylene
Benzene
Vinyl chloride
Trichloroethylene
Carbon Tetrachloride
Chlordane
Ethylene dibromide
Dioxane
Dichlorobutene
Benzo (a)pyrene
Chlorobenzilate
Chloroform
Toluene-2 , 4-dimaine
Benzyl chloride
Acrylonitrile
Vinylidene chloride
Benzidine
DDT
Ethylenimine
Chrysene
Methylene bis (chloroaniline)
Heptachlor
Tetrachloroe thane
Dichlorobenzidine
Epichlorohydrin
Dinitro toluene
Diaminoanisole
Trichlorofon
Captan
Benz (a) anthracene
Ethyl carbamate (urethane)
Dime thy Ihydrazine
Hydrazine
Nitrosodimethylamine
Bis (chloromethyl) ether
Aldrin (3.0 x 106)b
Polychlorinated biphenyls
(1.7 x 105)c
234 h
2.0 d
3.0 d
12 h
0.3 d
10 wk
N.A.a
20 h
9.6 h
N.A.
N.A.
N.A.
13 h
N.A.
N.A.
N.A.
24 h
1 d
N.A.
1.5 d
-
12 h
N.A.
N.A.
1 d
3 h
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
2.1 h
1 h
1 h
25 min
N.A.

N.A.
Emissions ,
kg/yr,
remaining
after 24 hours
9.1 x 107
8.5 x 107
5.9 x 107
3.0 x 107
1.7 x 107
1.6 x 106
9.6 x 106
2.1 x 106
1.3 x 106
8.7 x 10s
8.3 x 105
9.0 x 105
7.2 x 105
4.4 x 10s
4.1 x 105
3.7 x 10s
2.1 x 105
3.5 x 10"
1.9 x 10"
1.7 x 10*
1.7 x 10"
1.1 x 10"
1.1 x 10*
9.4 x 103
2.3 x 103
8.6 x 102
4.0 x 102
1.4 x 102
1.0 x 102
<1.0 x 102
<1.0 x 102
4.5
2.0
>1.0
>1.0
>1.0
0

0
   Persistence data could not be found.  Assumed that the chem-
   ical does not degrade appreciably in 24 hours.

  ^Current production assumed to be zero, but literature value
   also cited.
  'Primary source of biphenyl emissions was production of poly-
   chlorinated biphenyls, which has been stopped.  Average
   literature value given in parentheses.
                                22

-------
  TABLE 9.   EMISSIONS/PERSISTENCE-RANKED POSSIBLE CARCINOGENS


                                                   Emissions,
                                                     kg/yr,
                                    Atmospheric    remaining
Rank            Chemical             half-life   after 24 hours
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26

27
28
Dichloropropene
Pentachlorophenol
Methyl chloride
Styrene
Morpholine
Tetraethyl lead
Hexachlorobutadiene
1 , 1-Dichloroethane
Chloroprene
Di- (2-ethylhexyl) phthalate
Vinyl acetate
Hexachlorobenzene
Allyl chloride
Cumene hydroperoxide
Ethylene oxide
Methylenedianiline
Propylene oxide
Acrolein
Di-tert-Butyl peroxide
1-Naphthylamine
Mercaptobenzothiazole
Vinyl bromide
Dichloronaphthoquinone
Trichlorophenol
Nitrochlorobenzene
Dichlorovinyl dimethyl
phosphate
Formaldehyde ,
Biphenyl (9.2 x 10 ")

3
N.A
1
N
N

<
N
<1

N




N

2.

.
.
2
1
^
0
1
.
2
9
3
3
.
3
6
79
12
9.
N
N
N
N

N
1.
N
6
.
.
•
.

.
2
•
d
f a
yr
A.
A.
d
d
A.
h
d
A.
d
h
h
h
A.
h
h
h
h
h
A.
A.
A.
A.

A.
h
A.
2
2
1
5
5
4
3
2
1
1
6
1
1
8
3
2
1
1
1
8
4
4
9
5
3

2
45
0
.2
.1
.6
.6
.5
.7
.4
.6
.3
.2
.8
.6
.1
.2
.8
.6
.7
.1
.1
.0
.8
.0
.0
.0
.0

.0
.8

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

X


10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
7
7
7
6
6
6
6
6
6
6
5
5
5
4
14
4
**•
^
4
3
103
10
10
10
10

3
2
2
2

102





 N.A. - Persistence data could not be found.  Assumed that the
 chemical does not degrade appreciably in 24 hours.

 ^Primary source of biphenyl emissions was production of poly-
 chlorinated biphenyls, which has been stopped.  Average
 literature value given in parentheses.
                             23

-------
POTENCY OF POSSIBLE AND PROBABLE CARCINOGENS

It was decided that the potency of the possible and probable
carcinogens would be determined, where possible, by the average
of the mutagenic potency relative to benzo(a)pyrene using two
different mutagenic tests and the carcinogenic potency relative
to benzo(a)pyrene using two different species or routes of
administration.

Data required for potency calculations based on any specific test
system was unavailable for many compounds.  This is particularly
true for carcinogenic data; such information is often conflicting
when it can be found.  It is important, however, to take into
account the fact that some chemicals are more potent Carcinogens
than others.  Absolute potency data, however, should not be
required in order to determine the relative significance of a
number of chemicals.  Thus, a system to determine relative poten-
cies was devised.   Several decisions were made concerning how the
data would be treated:

(1)  Both mutagenic  and carcinogenic potencies would be used, with
    the final result being an average of the two numbers.

(2)  Missing data would be handled by using  an average potency
    determined from the rest of the compounds within each group
    (possible vs. probable).

(3)  Benzo(a)pyrene  was selected as the basis for comparisons
    because of the  large number of test systems in which it has
    been evaluated.

(4)  The relative carcinogenic potencies would be determined by
    comparing only  data from the same species and route of admini-
    stration.  For  example, if chlordane had been evaluated in
    hamsters by addition of the chemical to their food, only
    benzo(a)pyrene  data generated by the oral route on hamsters
    would be used to determine the relative potency of these two
    compounds.

(5)  When several sets of test data were available, the log average
    of the relative carcinogenic  (or mutagenic) potencies would
    be used to assure that results from any one test would not
    overshadow other results which were orders of magnitude
    different.

(6)  Average mutagenic potencies would be assigned to test com-
    pounds even  if  they were found to be negative by the test
    concerned.  For example, a logarithmic average of the Ames
    test data from  all of the compounds on both carcinogen lists
    (possible and probable)  has been found to be 8.3 x 10~3
    revertants per nanomole.  In our computations, this average
    mutagenic potency was arbitrarily assigned to all chemicals


                               24 '

-------
    that have been found positive on the Ames test with no data
    reported, or have been found negative on the Ames test.  This
    only assumes that unless other data are known, the chemical
    has an average potency.  For the viral enhancement data, the
    average potency of 4.1 x 10~3 yg/ml was assigned to chemicals
    for which there were no data.  The average of these two
    numbers gives a relative mutagenic potenty of 5.3 x 10~3 for
    any chemicals that have no mutagenic data cited in the
    literature.  Likewise, the average relative carcinogenic
    potency was found to be 1.4 x 10~2.

(7) In test systems where no benzo(a)pyrene data were available,
    secondary standards would be used to back calculate a potency
    relative to benzo(a)pyrene.

RELATIVE MUTAGENIC POTENCY

Efforts were made to assemble mutagenic potency data.  In addi-
tion to the data cited in Appendix A, some data are displayed in
Tables 10, 11, and 12.

              TABLE 10.  RELATIVE MUTAGENIC POTENCY
                   [Compared to benzo(a)pyrene]

s.
Chemical
Allyl chloride. [9]
DDT [10]
Diaminoanisole [11]
Dichlorovinyl dimethyl
phosphate [12]
Hydrazine [13]
Methyl chloride [14]
Tetrachloroethane [15]
Toluene-2 , 4-diamine [16]
Potency
, typhimurium
rev/nmole
61
0
5

1
0
0
0
0

.01
.66

.35
.043
.12
.008
.43
, Relative
potency
5
8
4

1
3
9
6
3
.0
.5
.7

.1
.6
.9
.4
.6
x
x
X

X
X
X
X
X
10
10
10

10
10
10
10
10
- 1
-5
— 2

-2
- t
— t
~5
-2

  [9] Mutation Research, 57:11-15, 1978.
 [10] Journal of Agricultural and Food Chemistry,  24:560,  1976
 [11] Biochemical Pharmacology, 26 (8):729-734 , 1977.
 [12] Mutation Research, 31:268-269, 1975.
 [13] Mutation Research, 40(2):73-83, 1976.
 [14] Mutation Research, 40 (3) :273-275 , 1976.
 [15] Cancer Research, 34:2576, 1974.
 [16] Proceedings of the National Academy of  Sciences of  the
     United States, 72 (6):2423-2427 , 1975.


                                25

-------
              TABLE  11.   PRELIMINARY MUTAGENIC  POTENCY DATA
Chemical
Acrylonitrile
Benz (a) anthracene
Benzidine
Benzo (a)pyrene
Benzyl chloride
Captan
Chlordane
Chrysene
Dichlorobenzidine
Dichlorobutene
Dime thy Ihydrazine
Ethylene dibromide
Ethylene dichloride
Ethylenimine
Heptachlor
Hydrazine
4,4-Methylene bis (2-
chloroaniline)
Nitrosodimethylamine
Vinyl chloride
Vinylidene chloride
Chloroprene
Formaldehyde
1-Naphthylamine
Pentachlorophenol
Propylene oxide
Tetraethyl lead
Vinyl acetate
Vinyl bromide
S. typhimurium ,
rev/mole
1.2 x 10~2
9.0 x 10~2
1.2 x 10~2
1
1.7 x 10-*
2.1 x 10~1

3.1 x 10-1

2.4 x 10~2

5.0 x 10-*

1.7 x 10~2



2.2 x 10-2
1.7 x 10-*
2.9 x 10-*
7.3 x 10-*
2.5 x 10-3

3.5 x 10~3




1.3 x 10-3
Viral
enhancement ,
pq/ml
8.0 x 10-*
1.6 x 10~2
1.6 x 10-*
1


1.6 x 10-2

6.4 x 10-3

3.2 x 10-
1.6 x 10-
1.6 x 10-

8.0 x 10-
8.0 x 10-

3.2 x 10-2
Negative
Positive

6.4 x 10-*
1.3 x 10~1
8.0 x 10-*
8.0 x 10-*
3.2 x 10-*
6.4 x lO"3
1.3 x 10-3

                TABLE 12.   OTHER  MUTAGEN  DATA TO  CONSIDER
            Drosojyhila mSlavogaster 117]

              Nj-trosodimethylamine
              JDimethy Ihydr az ine
              'DDT
              Ethylene dibromide
              Vinyl chloride

            Sacchoapomyces cerevisiae [18]

              Dichlorovinyl dimethyl
                phosphate
              Pentachlorophenol

              Ethylene dibromide

              Captan
recessive lethal mutations at 6.8 nmole
recessive lethal mutations at 2.0 nmole
recessive lethal mutations at 0.14 nmole
recessive lethal mutations at 0.3 nmole
causes recessive lethal mutations
19 mole for 6 h gives 11.7 ade2 and
29 trp5 mutants
0.19 mole for 6 h gives 6.6 ade2 and
4.3 trp5 mutants
0.17 mole for 27 h gives 10.8 ade2 and
8.8 trp5 mutants
0.17 mole for 27 h gives 12.5 ade2 and
17.7 trp5 mutants
[17]  International Agency  for  Research on Cancer  Scientific Pub-
      lication No.  12,  1976.   pp.  61,  125,  and  623.
[18]  International Agency  for  Research on Cencer  Scientific Pub-
      lication No.  10,  1974.   pp.  161-181.
                                         26

-------
RELATIVE CARCINOGENIC POTENCY

A major problem encountered is that differing routes of admini-
stration may cause the potency relative to benzo(a)pyrene to vary
by as much as 106.  For example, benzene on mouse skin has a
toxic dose low  (TDLo) of 1,200 g/kg  (over a 49-week period),
while benzo (a)pyrene has a TDLo of 2 yg/kg for a relative potency
of 2 x 10~9.   Subcutaneously, 1 mg/kg benzene has been suggested
to cause cancer (no controls) versus 0.004 mg benzo (a)pyrene for
a relative potency of 4 x 10~3 and a difference in potency of six
orders of magnitude.  In spite of the problems associated with
this type of calculation, an average mutagenic potency and an
average carcinogenic potency was calculated for each chemical, as
shown in Tables 13 and 14.  The log average of these two numbers
was then determined as also shown in Tables 13 and 14.

PRIORITIZATION OF POSSIBLE AND PROBABLE CARCINOGENS

Since this project is directed at atmospheric carcinogens, some
consideration should be given to whether a specific chemical is
much more likely to be found in the" air, in water, or in the soil
or other solids.  Many different parameters could be used to put
more emphasis on chemicals which are atmospheric pollutants such
as whether the chemicals at ambient temperature are solids,
liquid, or a gas.  The solid-liquid-gas classification would not
distinguish between highly volatile liquids such as chloroform
and benzene and liquids with very low vapor pressures such as the
polychlorinated biphenyls.  Since boiling point data are readily
available and correlate well with vapor pressure, it was thought
that boiling point might be a valid parameter to consider.  On
the other hand, solids might be in the atmosphere as particulate
matter or carried on other particulates.  Thus it was decided not
to include these data in the prioritization model.  Many data on
various properties of the selected possible and probable carcino-
gens, however, are listed in Appendix A for each chemical.

The prioritization model that was used to determine which sig-
nificant carcinogens in the atmosphere should be sampled for this
project results in an equivalent kilograms of benzo(a)pyrene
emitted per year after 24 hours in the atmosphere.  This number
is generated by multiplying:   (a) the kilograms emitted per
year,       times  (b) the fraction present after 24 hours, times
(c) the potency relative to benzo(a)pyrene.

From the top chemicals in these prioritizations, 20 chemicals
were selected which represent a variety of chemical types.  Of
these 20 chemicals, 15 will be selected by EPA for use in the
latter portions of this contract and contract 68-02-2774  (port-
able carcinogen tester) as key chemicals in the analysis of
ambient air.   These are footnoted on Tables 15 and 16, which
rank the probable and possible carcinogens by equivalent emis-
sions of benzo (a)pyrene after 24 hours.


                                27

-------
        TABLE  13.   RELATIVE  MUTAGENIC/CARCINOGENIC POTENCY
                      OF  PROBABLE  CARCINOGENS
                      [Compared to benzo(a)pyrene]

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Chemical
Benzo (a) pyrene
DDT
Heptachlor
Nitrosodimethylamine
Aldrin
Benz (a) anthracene
Polychlorinated biphenyls
Bis (chloromethyl) ether
Ethylenimine
Chloroform
Diaminoanisole
Trichlorfon
Carbon tetrachloride
Dichlorobenzidine
Ethylene dibromide
Dinitro toluene
Tetrachloroethylene
Captan
Toluene-2 , 4-diamine
Vinylidene chloride
Benzene
Dichlorobutene
Acrylonitrile
Trichloroethylene
Methylene bis (chloroaniline)
Ethylene dichloride
Chlordane
Ethyl carbamate (urethane)
Chrysene
Vinyl chloride
Tetrachloroe thane
Dioxane
Ch lor obenzi late
Epichlorohydrin
Dimethylhydrazine
Hydrazine
Benzidine
Benzyl chloride
Mutagenicity
compared to B(a)P
1.0
-(5.8
8.1
8.3
(5.8
3.8
(5.8
+ (5.8
8.3
(5.8
1.4
(5.8
-(5.5
1.1
2.8
(5.8
(5.8
5.6
1.2
1.7
(5.8
9.9
4.5
6.0
2.7
1.2
1.2
-(5.8
3.6
2.5
3.1
(5.8
(5.8
+ (5.8
5.2
1.7
1.4
8.3

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
K
10-3)a,b
10~3
10-"
io-3)
io-2
ID"3)
10-3)C
IO-3
ID"3)
io-2
ID-3)
lO-3)
io-1
10-"
lO-3)
lO-3)
io-2
io-2
lO-3
lO-3)
ID"3
10-"
ID"3
io-2
ID"3
io-2
lO-3)
io-2
10-3
io-*
io-3)
io-3)
ID"3)
lO-3
10-"
10~3
10-"
Carcinogeni city
compared to B(a)P
1
3
1
11
5
3
8
7
4
5
+ (1
2
2
8
0
+ (1
+ (1
7
2
+ (1
4
2
5
3
7
+ d
8
1
2
3
+ (1
6
6
4
4
1
6
1
.0
.7
.8
.0
.0
.0
.0
.0
.6
.0
.4
.8
.5
.1
.31
.4
.4
.8
.9
.4
.0
.3
.0
.1
.0
.4
.7
.8
.5
.0
.4
.2
.0
.0
.6
.2
.5
.3




X
X
X
X
X
X
X
X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X




io-1
io-2
io-2
io-2
io-2
io-2
io-2)
10 ~'a
lo-2
10-*

10~2)
io-2)
io-"
IO-3
io-2)
io-3
lO-3
io-2
ID"3
io-«
io-2)
10-"
IO-3
IO-2
lO-3
io-2)
io-*
io-*
10-*
io-*
IO-2
10-*
10-"
Average
mutagenic/
carcinogenic
potency
1.0
1.5
1.2
9.6
5.4
3.4
2.2
2.0
2.0
1.7
1.4
1.3
1.2
9.4
9.3
9.0
9.0
6.6
6.0
4.9
4.8
4.8
4.7
4.3
4.3
4.1
3.2
3.2
3.0
2.7
2.1
1.9
1.9
1.5
1.5
1.4
9.5
3.3

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

io-1
io-1
lO-2
lO-2
io-2
lO-2
io-2
io-2
io-2
io-2
ID"2
lO-2
io-3
lO-3
io-3
IO-3
ID"3
lO-3
io-3
lO-3
lO-3
ID"3
io-3
io-3
io-3
io-3
lO-3
io-3
io-3
lO-3
ID"3
lO-3
lO-3
lO-3
lO-3
10-"
io-"
Parentheses  indicate that no  statistical data were available, so an average potency
was used.

A minus  indicates that the chemical was not a mutagen by the test reported.

A plus indicates that the chemical was positive  on the test, but no numerial data
were reported.
                                       28

-------
           TABLE  14.   RELATIVE MUTAGENIC/CARCINOGENIC  POTENCY OF POSSIBLE  CARCINOGENS
                                      [Compared to benzo (a)pyrene]
ISJ

1
2
3
4
5
6
7
8
9

10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Chemical
Hexachlorobenzene
Formaldehyde
Tetraethyl lead
Dichlorohaphthoquinone
Allyl chloride
Chloroprene .
Mercaptobenzothiazole
Hexachlorobutadiene
Dichlorovinyl dimethyl
phosphate
Pentachlorophenol
Nitrochlorobenzene
Styrene
Acrolein
Ethylene oxide
1 , 1-Dichloroethane
Dichloropropene
Di- (2-ethylhexyl) phthalate
Vinyl acetate
Methylenedianiline
Vinyl bromide
Morpholine
Methyl chloride
Di-tert-butyl peroxide
1-Naphthylamine
Propylene oxide
Trichlorophenol
Cumene hydroproxide
Biphenyl
Mutagenicity
compared to B(a)P
(5.8
3.3
7.3
(5.8
4.5
1.3
(5.8
(5.8

1.1
2.6
(5.8
+ (5.8
+ (5.8
(5.8
+ (5.8
(5.8
(5.8
3.3
+ (5.8
2.3
(5.8
2.0
(5.8
1.7
1.6
(5.8
-(5.8
(5.8
X
X
X
X
X
X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
lO-3)9
lO-2
lO-3
lO-3)
lO-2
lO-3
lO-3)
lO-3)

lO-2
lO-3
lO-3)
10~3)C
lO-3)
lO-3)
lO-3)
ID"3)
lO-3)
10~3
lO-3)
lO-3
lO-3)
lO-3
lO-3)
lO-3
lO-3
ID"3)
lO-3)
ID"3)
Carcinogenicity
compared to B(a)P
5.
5.
1.
1.
-d.
6.
5.
3.

-d.
7.
-d.
-d.
-d.
+ d.
-d.
-d.
i.
-d.
i.
-d.
7.
-d.
6.
1.
1.
6.
3.
7.
9
9
7
7
9
4
2
9

9
6
9
9
9
9
9
9
3
9
1
9
3
9
0
7
4
1
5
6
X
X
X
X
X
X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
io-1
ID"3
lO-2
lO-2
ID"3 )
lO-2
ID"3
ID"3

ID"3)
ID"3
lO-3)
lO-3)
lO-3)
lO-3)
lO-3)
lO-3)
10~3
lO-3)
lO-3
10~3 )
10-*
ID"3)
10-*
lO-3
10"*
io-5
10"5
io-6
Average
mutagenic/
carcinogenic
potency
5.8
1.4
1.1
9.9
9.3
9.1
5.5
4.8

4.6
4.0
3.3
3.3
3.3
3.3
3.3
3.3
2.7
2.5
2.5
2.1
2.1
2.0
1.9
1.7
4.7
5.9
4.5
2.1
X
X
X
X
X
X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
10-2
ID"2
IO""2
ID"3
ID"3
ID"3
ID"3
ID"3

10"3
10~3
ID"3
IO-3
ID"3
10"3
ID"3
ID"3
ID"3
ID"3
ID"3
ID"3
ID"3
lO-3
ID"3
lO-3
10-*
10-*
10-*
10-*

            Parentheses indicate that no statistical data were available, so an average potency
            was used.
            A minus indicates that the chemical  was not a mutagen by the test reported.
           CA plus indicates that the chemical was positive on the test, but no numerial data
            were reported.

-------
TABLE 15.   RANKING  OF  PROBABLE  CARCINOGENS  BY  EQUIVALENT
               EMISSIONS OF B(a)P AFTER  24  HOURS

Chemical
Benzo (a)pyrene
Tetrachloroethylene
Ethylene dichloride
Benzene
Carbon tetrachloride
Vinyl chloride
Trichloroethylene
Chlordane
Ethylene dibrornide
Chloroform
Dichlorobutene
Toluene- 2 , 4-diamine
DDT
Dioxane
Acrylonitrile
Chlorobenzilate
Heptachlor
Vinylidene chloride
Ethylenimine
Benzyl chloride
Chrysene
Methylene bis (chloroaniline)
Benzidine
Dichlorobenzidine
Tetrachloroethane
Dinitro toluene
Benz (a) anthracene
Diaminoanisole
Epichlorohydrin
Trichlorfon
Captan
Nitrosodimethylamine
Bis (chloromethyl) ether
Ethyl carbamate (urethane)
Dimethylhydrazine
Hydrazine
Aldrin (3.0 x 106)C
Polychlorinated biphenyls
(1.7 x 105)c
Emissions,
kg/yr ,
remaining
after 24 hours
8
8
9
5
1
3
1
9
2
7
8
4
1
1
3
9
1
2
1
4
1
1
3
2
9
4
<1
1
8
1
<1
>1
<1
4
2
>1
0

0
.3
.5
.1
.9
.6
.0
.7
.6
.1
.2
.7
.4
.9
.3
.7
.0
.1
.1
.7
.1
.7
.1
.5
.3
.4
.0
.0
.4
.6
.0
.0
.0
.0
.5
.0
.0



x
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X








10s3
IO73
107a
1073
1073
IO7
IO7
IO6
10eb
IO5
10s
10s3
10*
IO63
10s3
10s
10*
10s
10*
10s3
lO^cl
10^*
lO^cl
IO3
IO3
IO2
IO2
IO2
IO2
IO2
IO2








Average
mutagenic/
carcinogenic
potency
1
9
4
4
1
2
4
3
9
1
4
6
1
1
4
1
1
4
2
3
3
4
9
9
2
9
3
1
1
1
6
9
2
3
1
1
5

2
.0
.0
.1
.8
.2
.7
.3
.2
.3
.7
.8
.0
.5
.9
.7
.9
.2
.9
.0
.3
.0
.3
.5
.0
.1
.0
.4
.4
.5
.3
.6
.6
.0
.2
.5
.4
.4

.2

x
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

X

ID"3
1Q-3
ID-3
lO"2
ID-3
ID"3
ID"3
lO-3
io-2
ID"3
io-3
io-1
lO-3
lO-3
lO-3
io-1
IO-3
ID"2
10-*
io-3
io-3
10-*
lO-3
lO-3
io-3
io-2
io-2
io-3
ID"2
10~3
lO-2
lO-2
io-3
lO-3
ID"3
ID"2

10-2
Average x kg
remaining
after
24 hours
8.
7.
3.
2.
1.
8.
7.
3.
2.
1.
4.
2.
2.
2.
1.
1.
1.
1.
3.
1.
5.
4.
3.
2.
2.
3.
<3.
2.
1.
1.
<6.
>9.
>2.
1.
3.
XL.
0

0
3
7
7
8
9
2
3
1
0
2
2
6
8
5
8
7
3
0
4
4
1
8
3
1
0
6
4
0
3
3
6
6
0
5
0
4



x IO5
x IO5
x 10s
x 10s
x IO5
x 10*
x 10*
x 10*
x 10*
x 10*
x 103
x IO3
x IO3
x IO3
x IO3
x IO3
x IO3
x IO3
x 102
x IO2
x IO1
x IO1
x IO1
x IO1
x IO1





x 10~1
x 10"2
x ID"2
x 10"2
x ID"3
x ID"3




 One  of  20  significant carcinogens which were selected for variety of chem-
 ical type  and high ranking in prioritization.

 As of 22 February 1979, MRC has recommended that tetraethyl lead and cumene
 hydroperoxide be dropped from the list of 20 and replaced by ethylene
 dibromide  and dichloropropene.

"Now  out of production.
                                     30

-------
   TABLE  16.   RANKING OF  POSSIBLE  CARCINOGENS BY  EQUIVALENT
                EMISSIONS OF B(a)P AFTER  24 HOURS
         Chemical
  Emissions,
    kg/yr,
  remaining
after 24 hours
  Average
 mutagenic/
carcinogenic
  potency
Average x kg
 remaining
   after
  24 hours
Pentachlorophenol
Dichloropropene
Tetraethyl lead
Methyl chloride
Styrene
Hexachlorobutadiene
Chloroprene
Morpholine
Hexachlorobenzene
1 , 1-Dichloroethane
Di- (2-ethylhexyl) phthalate
Vinyl acetate
Allyl chloride
Ethylene oxide
Methylenedianiline
Cumene hydroproxide
Acrolein
Mercaptobenzothiazole
Di-tert-butyl peroxide
1-Naphthylamine
Dichloronaphthoquinone
Vinyl bromide
Propylene oxide
Dichlorovinyl dimethyl
phosphate
Nitrochlorobenzene
Formaldehyde
Trichlorophenol
Biphenyl (9.2 x 10*)
2
2
4
1
5
3
1
5
1
2
1
6
1
3
2
8
1
4
1
8
9
4
1

2
3
45
5
0
.1
.2
.7
.6
.6
.4
.3
.5
.6
.6
.2
.8
.1
.8
.6
.2
.1
.8
.1
.0
.0
.0
.7

.0
.0
.8
.0

x
x
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

X
X

X

107a
lO7^
ioea >k
IO7
106a
106a
IO6
IO6
IO5
IO6
106a
10sa
IO5
10*a
10*
10*a'b
10*a
IO3
10*
IO3
IO2
IO3
10*

IO2
IO2

IO2

4
3
1
2
3
4
9
2
5
3
2
2
9
3
2
4
3
5
1
1
9
2
4

4
3
1
5
2
.0
.3
.1
.0
.3
.8
.1
.1
.8
.3
.7
.5
.3
.3
.5
.5
.3
.5
.9
.7
.9
.1
.7

.6
.3
.4
.9
.1
x
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

X
X
X
X
X
io-3
io-3
io-2
io-3
10~3
io-3
io-3
io-3
10"2
10~3
io-3
10~3
io-3
io-3
io-3
10-*
io-3
io-3
io-3
io-3
io-3
io-3
10-*

io-3
io-3
io-2
10~*
10-*
8.x
7.3
5.2
3.1
1.9
1.6
1.2
1.1
9.4
8.6
3.3
1.7
1.0
1.3
6.6
3.7
3.6
2.6
2.1
1.4
8.9
8.4
8.0

9.2
6.6
6.4
3.0
0
x
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X




X
X
X
X

10*
10*
10*
10*
10*
10*
10*
10*
IO3
IO3
IO3
IO3
IO3
IO2
IO1
IO1
IO1
IO1
IO1
IO1




IO1
10~1
10~1
io-1


One of 20 significant carcinogens which were selected for variety of  chem-
ical type and high ranking in prioritization.
As of 22 February 1979, MRC has recommended that tetraethyl lead and  cumene
hydroperoxide be dropped from the list of 20 and replaced by ethylene
dibromide and dichloropropene.
                                   31

-------
                            SECTION 5

        STATE-OF-THE-ART REVIEW OF CARCINOGENIC COFACTORS
Because a portion of this contract was to be devoted to the
determination of the effects of carcinogenic cofactors, a litera-
ture search was conducted that resulted in a review of the state
of the art of carcinogenic cofactors.   This review concentrated
on the effects of various industrial chemicals on the carcino-
genic potential of other industrial chemicals.  It also lightly
reviewed other cofactor effects such as physiological  (e.g.,
hormonal), genetic, medical (e.g., disease states), environmental
(e.g., light), dietary, and other factors that affect the initia-
tion or growth of cancers.

Some of the key words or word stems utilized in this computer
search were:  cocarcinogen...  or co-carcinogen...
              syncarcinogen...

Other words or word stems which were used in conjunction with
carcinogen... included:  modifier...
                         promoter...
                         inhibitor...
                         enhances...
                         synergy or synergism

Among the National Library of Medicine data bases, MEDLINE, TOX-
LINE, CANCERLINE, and CANCERPROJ were search.  On the SDC system,
CHEMCON  (chemical abstracts) was searched.  The total number of
literature citations printed off line was 2,327; the percentages
from the various data files were:  MEDLINE, 10%; TOXLINE, 40%;
CANCERLINE, 45%, CANCERPROJ, 2%; and CHEMCON, 3%.  These  abstracts
were reviewed along with several books and other reference papers.
A summary of the "state of the art" of carcinogen cofactors is
included in Appendix B, "A Review of the Carcinogen Cofactor
Literature."
                               32

-------
                            SECTION 6

                 CARCINOGEN ISOPLETH GENERATION
A portion of the effort in the first phase of this contract was
to be devoted to determining the location of optimum sampling
sites in four cities where field validation of the sampling and
analysis equipment and techniques is to occur (Houston, Los
Angeles, Birmingham, and Newark).

In order to accomplish this task, the MRC Source Assessment Data
Base was used to obtain most of the necessary input for the EPA
Climatological Dispersion Model  (COM).

Meterological data from the National Climatic Center (STAR com-
puter program) were reviewed for Houston, Los Angeles,  Newark,
and Birmingham.  These data consisted of joint frequencies of
occurrence of wind direction, wind speed, and atmospheric
stability  (Pasquill stability classes).

It was decided that only one set of isopleths would be  generated
for each of the target cities and that it would include the total
mass of those carcinogenic chemicals included on the MRC Source
Assessment Data Base that are emitted in these cities.

This decision reflects the purpose of these particular  isopleths:
to aid in the selection of sampling sites to be used in evalua-
ting the portable and high-volume sampler systems.  For this
purpose, the important factor is the mass of emissions, not the
potency of the carcinogens.

The chemicals included in the study are from the list of probable
chemical carcinogens generated earlier in the project.   The prob-
able carcinogens are generally chemicals for which animal studies
have been positive, with supporting mutagenic data, or for which
government regulations have been promulgated that require the
chemical to be handled as a carcinogen regardless of the animal
data.

The chemicals were selected from the list of probable carcinogens
ordered according to annual mass of emissions released to the
environment corrected for atmospheric degradation after 24 hours.
From the top 30 chemicals, 19 were on the source assessment data
base.  Many of the other 11 chemicals are pesticides that are
                               33

-------
currently being phased out of production.  The 19 chemicals
selected for evaluation are shown along with the target cities  in
which they are found in Table 17.

     TABLE 17.   CHEMICALS IN TOP 30 PROBABLE CARCINOGENS ON
                MRC DATA BASE THAT ARE FOUND IN FOUR CITIES3
       Compound
Houston   Newark
         Los
       Angeles
       Birmingham
 Ethylene dichloride
 Ethylene dibromide
 Vinyl chloride
 Chloroform
 Carbon tetrachloride
 Vinylidene chloride
 Benzene
 Aerylonitrile
 Dichlorobutene
 Trichloroethylene
 Tetrachloroethane
 Epichlorohydrin
 Benzyl chloride
 Polyvinylidene
 DDT
   X
   X
   X
   X
   X
   X
   X
   X
   X
   X
   X
X
X
X
X
X
X
            X
            X
            X
X

X
X
X
X
X
X
                      X
  From annual emissions in the United States that remain after
  24 hours.

All sources of emission were located on maps in Universal Trans-
verse Mercator  (UTM) coordinates for the four cities.  The input
data were gathered and keypunched.  The conversion from street
addresses to UTM coordinates were more difficult and time con-
suming than originally estimated.  The Houston area was selected
for the first simulated dispersion modeling.

Annual meterological data  (from the STAR computer program [19]
for Houston were initially used with a coarse grid of about
50 x 50 km  (in about 2-km intervals) with approximately 625
receptor points.  The average stack heights used were as listed
in the MRC Source Assessment Data Base  (SADB) [1].  Annual pro-
duction rates and emission factors were also from the SADB.
 ;i9] Seasonal & Annual  (Day/Night) Wind Distribution by Pasquill
     Stability Classes  (6), STAR Program.  U.S. Department of
     Commerce, National Oceanic and Atmospheric Administration,
     Environmental Data Service, National Climatic Center,
     Asheville, North Carolina, July 15, 1977.
                               34

-------
Average mixing depths were from a paper by Holzworth  [20].  The
average annual Houston temperature of 21.11°C was from the Sta-
tistical Abstract of the United States  [21].  A stack diameter
of 0.30 m was estimated by MRC personnel.  Exit velocities for
given stack diameters and flow rates were found for a typical
process [22, 23].  A gas exit temperature of 38°C was assumed.
Environmental persistence was assumed to be a 1-week half-life
(essentially nondegrading for this model).  The appropriate
maximum was located; then the area around the maximum was "fine
tuned" and rerun for the final isopleth to be plotted.  A three-
dimensional concentration isopleth was made.

Along with the other sources of pollution, there were eight point
sources for ethylene dichloride and five for vinyl chloride in
the Houston area.  All were located in Deer Park and Pasadena,
southwest of Houston.  The companies from which the emissions
occur are primarily Shell Chemical Company, Ethyl Corporation,
and Diamond Shamrock Company.

A preliminary computer run was conducted using only the ethylene
dichloride and vinyl chloride data for Houston.  The EPA COM  [24]
was used for the computerized analysis.  Initial results with a
relatively coarse grid show the maximum total pollution about
1 km north of the Shell plant.  A map of this area with a ground-
level isopleth of 500 yg/m3 for ethylene dichloride is shown in
Figure 1.  Listings of the COM input parameters and computer out-
put are shown in Figures 2 and 3.

In the parameters on the first sheet of Figure 2, sigma Z is the
standard deviation of the vertical wind profile.  The joint fre-
quency function indicates the wind direction and stability class
 [20] Holzworth, G. C.  Estimates of Mean Maximum Mixing Depths
     in the Contiguous United States.  Monthly Weather Review,
     92(5):235-242,  1964.

 [21] Statistical Abstract of the United States, 97th Edition.
     U.S.  Bureau of  the Census, Washington, D.C., 1976.  p. 161.

 [22] Khan, Z. S., and T. W. Hughes.  Source Assessment:  Poly-
     vinyl Chloride.  EPA-600/2-78-004i, U.S. Environmental
     Protection Agency, Cincinnati, Ohio, May 1978.  105 pp.

 [23] Scientific and  Technical Assessment Report on Vinyl Chloride
     and Polyvinyl Chloride.  EPA-600/6-75-004, U.S. Environmen-
     tal Protection  Agency, Washington, D.C., December 1975.
     130 pp.
 [24] Busse, A. D., and J. R. Zimmerman.  User's Guide for  the
     Flimatological  Dispersion Model.  EPA-R4-73-024, U.S.
     Environmental Protection Agency, Research Triangle Park,
     North Carolina, December 1973.  144 pp.


                               35

-------
CO
cr\
                                             POINT(

                                              CONCENTRATION
                                               MAXIMUM
                                                              Jp«»rtfl09<"1 \ 7*^A
.,  _        ?vJ  EMISSION SOURCESDeerPark
 %•'*>    Yf-L.j.H*".
 \'    •       s'
              5
              ^•i
                         Figure 1.   Ethylene dichloride  concentrations
                                    in Houston,  Texas  at 500  pg/m3
                                    (3 km/cm) .

-------
                                       COM VERSION 7:
        0.23^00oE+03        0.120000E+02
THE SIGMA Z COEFFICIENT TABLE  (G):
        0.253900E-03        0.253900E-03        0.383000E-01        0.208860E+01        0.208860E+01
        0.193600E-01        0."*93600E-01        0.139300E+00        0.111370E+01        0.111370E+01
        O.llS'tOOE + OO        0.10mOOE + 00        0.112000E + 00        0.910900E + 00        0.926000E + 00
        0.736800E+00        0.259100E+00        0.856000E-01        0.56^200E+00        0.686900E+00
        0.129690E+01        0.252700E+00        0.818000E-01        0 .f»2100E + 00        0,
     0.128120E+01
     0.9t6700E-fOO
     0.910000E+00
     0.865000E+00
     0.815500E+00

(continued)
                                         Figure  2.    Input  data.

-------
                      SECTOR
                                                             COM VERSION
                                                                                RUN
                                                     U2
                                                                        U3
                                                                                           Ut
                                                                                                              U5
                                                             THE JOINT FRESUENCY FUNCTION FOR STABILITY CLASS  1
u>
CO
                       1
                       2
                       3
                       t
                       5
                       6
                       7
                       8
                       9
                      10
                      11
                      12
                      13
                      It
                      15
                      16
 1
 2
 3
 4
 5
 6
 7
 e
 9
10
11
12
13
It
15
16
                       1
                       2
                       3
                       t
                       5
                       6
                       7
                       a
                       9
                      10
                      11
                      12
                      13
                      It
                      15
                      16
O.H60000E-03
0.280000E-03
0.320000E-03
0.510000E-03
0.129000E-02
0.5tOOOOE-03
0.880000E-03
0.800000E-03
0.118000E-02
0.780000E-03
0.630000E-03
0.680000E-03
0.710000E-03
0.270000E-03
0.380000E-03
0.t50oOOE-03
0.22tOOOE-02
0.20toOOE-02
0.219000E-02
0.237000E»02
0.321000E-02
0.2t5000E-02
0.226000E-02
0.212000E-02
0.319000E-02
0.205000E-02
0.132000E-02
0.139000E-02
0.176000E-02
0.980000E-03
0,9tOOOOE-03
0.980000E-03
          0.700000E-03
          0.520000E-03
          0.105000E-02
          0.900000E-03
          0.107000E-02
          0.115000E-02
          0.103000E-02
          0.960000E-03
          0.12.7000E-02
          0,t90oOOE-03
          0,tOOOOOE-03
          O.ttOoOOE-03
          0.650000E-03
          0.360000E-03
          0.280000E-03
          0.t90oOOE-03
0.250000E-OJ
0.270000E-03
0.210000E-03
0.370000E-03
0.730000E-03
0.600000E-03
0.550000E-03
0.570000E-03
0.126000E-02
0.390000E-03
0.640000E-03
0.530000E-03
0.530000E-03
0.2SOOOOE-03
O.ltOOOOE-03
0.210000E-03
THE
0.179000E-02
0.172000E-02
0.167000E-02
0.206000E-02
0.3tlOOOE-02
0.311000E-02
0.252000?- 02
0.261000E-02
0.332000E-02
0.195000E-02
0.163000E-02
0.188000E-02
0.208000E-02
O.taOOOOE-03
0.730000E-03
0.137000E-02
THE
0.231000E-02
0.135000E-02
0.229000E-02
0.17HOOOE-02
0.309000E-02
0.273000E-02
0.298000E-02
0.2t3000E-02
0.33tOOOE-02
0.121000E-02
0.620000E-03
0.12tOOOE-02
0.1t9000E-02
0.890000E-03
0.870000E-03
0.121000E-02
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0,0
0.0
0.0
0,0
0.0
JOINT FREOUENCY FUNCTION
O.eOOOOOE-02
0.760000E-03
0.980000E-03
0.112000E.02
0.286000E-02
0.220000E-02
0.172000E-02
0.135000E-02
0.298000E-02
0.9HOOOOE-03
0.105000E-02
0.115000E-02
0.800000E-03
0.230000E-03
0.270000E-03
0.550000E-03
JOINT FRE8UENCY FUNCTION
0.3&OOOOE-02
0.316000E-02
0.369000E-02
0.357000E-02
0.622000E-02
0.675000E-02
0.609000E-02
0.696000E-02
0.123200E-01
0.318000E-02
0.220000E-02
0.190000E-02
0.277000E-02
0.103000E-02
0.169000E-02
0.179000E-02
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
FOR STABILITY CLASS
0.0
0.0
0.0
0.0
0.0
0,0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
FOR STABILITY CLASS
0.370000E-03
O.ttOOOOE-03
0.270000E-03
O.ltOOOOE-03
0.920000E-03
0.690000E-03
0.6tOOOOE-03
0.1t7000E-02
0.252000E-02
0'.ttOOOOE-03
0.210000E-03
0.180000E-03
0.270000E-03
0.250000E-03
0.160000E-03
0.250000E-03
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0,0
0.0
0.0
0.0
0.0
0.0
2
0.0
0.0
0.0
0.0
0.0
0.0
0,0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
3
0.200000E-Ot
0.200000E-Ot
0.0
0.0
0.0
0.0
0.0
0,0
O.ltOOOOE-03
0,200000E-Ot
0.0
0.0
0.0
0.200000E-Ot
0.0
0.0
                                                                                                         0.0
                                                                                                         o.c
                                                                                                         0.0
                                                                                                         0.0
                                                                                                         0.0
                                                                                                         0.0
                                                                                                         0.0
                                                                                                         0,0
                                                                                                         0.0
                                                                                                         0.0
                                                                                                         0,0
                                                                                                         0,0
                                                                                                         0.0
                                                                                                         0.0
                                                                                                         0.0
                                                                                                         0.0
0.0
0.0
O.G
0,0
0.0
0,0
0.0
0,0
0.0
0.0
0,0
0,0
0.0
0,0
0.0
0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0,0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                               0.0
                                                                                                                 (continued)
                                                             Figure  2  (continued)

-------
LO
                 SECTOR
                  1
                  2
                  3
                  02
0.289000E-02
0.282000E-02
0.291000E-02
0.334000E-02
0.149000E-02
0.800000E-03
0.980000E-03
0.124000C-02
0.600000E-03
0.890000E>03
0.119000E-02
0.630000E-02
0.458000E-02
0.i»19000E.02
0.121000E-02
0.824000E-02
0.699000E-02
0.551000E-02
0.786000E-02
0.127100E-01
0.264000E-02
0.160000E.02
0.920000E-03
O.lttOOOE-02
O.T60000C.03
0.181000E.02
0.302000E-02
0.792000E-02
0.3e2000E-02
0.259000E-02
0.222000E-02
0.621000E-02
0.663000E-02
0.«12000E-02
0.994000E-02
0.18*tOOE-01
0.361000E-02
0.131000E-02
0.760000E-03
0.128000E-02
0.121000E-02
0.273000E.02
0.t«1000E-02
0.890000E-03
0.300000E-03
0.700000E-04
0.270000E-03
0.530000E-03
0.690000E-03
O.S30000E-03
0.940000E-03
0.20tOOOE-02
0.300000E-03
0.180000E-03
0.200000E-0*
0.160000E-03
0.210000E-03
0.101000E-02
0.142000E-02
0.180000E-03
0.0
0.0
0.0
0.500000E.OH
0.0
0.200000E-01*
0.200000E-0*
0.230000E.03
0.0
0.0
0.0
0.110000E-03
0.1»OOOOE-03
0.110000E-03
O.SOOOOOE.O*
1
2
3
H
5
6
7
8
9
10
11
12
13
It
15
16
0.230000E-02
0.189000E-02
0.242000E-02
0.197000E-02
0.370000E-02
0.236000E-02
0.220000E-02
0.308000E-02
0.362000E-02
0.101000E-02
0.660000E-03
0.350000E-03
0.550000E-03
0.390000E-03
0.620000E-03
0.960000E-03
0.279000E-02
0.227000E-02
0.222000E-02
0.195000E-02
0.126000E-02
0.270000E-02
0.295000E-02
0.3t6000E-02
0.183000E-02
0.920000E-03
O.H60000E-03
O.itlOOOOE-03
0.500000E-OJ
0.480000E-03
0.<410000E-03
0.12HOOOE-02
0.90SOOOE.02
0.5'»7000E-02
0.460000E-02
0.339000E-02
0.628000E-02
0.7HOOOOE.02
0.726000E-02
0.106300E-01
0.119100E-01
0.227000E-02
0.890000E-03
0.460000E-03
0.620000E-03
0.500000E.03
0.1t7000E.02
0.360000E-02
0.870000E-02
0.263000E-02
0.140000E-Q2
0.105000E-02
0.199000E-02
0.3110bOE-02
0.218000E.02
0.497000E-02
0.453000E-02
0.410000E-03
0.210000E-03
0.320000E-03
0.320000E-03
0.780000E-03
0,17tOOOE-02
0,!*97000E-02
0.10SOOOE-02
0.230000E-03
0.900000E-01*
0.110000E-03
0.160000E-OS
0.210000E-05
0.110000E-03
0.230000E-03
0.900000E-OH
0.200000E-0>»
0.0
0.200000E-OH
0.200000E-04
0.140000E.03
0.410000E>03
0.112000E-02
0.900000E-0»
0,0
0.200000E.O*
0,0
O.TOOOOOE-O'*
0.250000E-OB
0.200000E.O*
0.700000E-Ot
0.200000E-0*
0.0
0.0
o.o
0,0
0.230000E.03
0.110000E-03
0.160000E-03
0.0
0.0
0.0
0.0
0.0
0.0
0,0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0,0
0.0
                                                                                                               [continued)
                                                          Figure  2  (continued)

-------
SOURCE INPUT
X
0.90000E+02
0.90000E+02
0.90000E+02
0.9HOOOE+02
0,96700E+02
0.0
0.0
0.0
0.0
0.72000E-05
O.'iOOOOE.O'*
0.92000E-05
SH
0.15700E+02
0.30500E+02
0.27tOOE+02
0,t570aE+02
0,30500E+02
0.27"*OOE*02
0.30500E+02
0.27"»OOE + 02
0.12200E+02
0.12200E+02
0.12200E+02
D
O.lSOOOE+Ol
0.10000E+01
o.iooooe+oi
0.16000E+01
0.10000E*01
0.10000E+01
0.10000E+01
0.10000E+01
0.50000E+00
0,50000E<-00
O.SOOOOE-t-00
VS
0.90000E-01
0.15000E+01
o.msooE+oi
0.9tOOOE-01
0.15000E+01
0.1SOOOE*01
0.15000E+01
0.1"»300E + 01
0.57500E+OJ
O.STSOOE+Ol
0.57500E+01
T
O.S6000E»02
0.38000E-5-02
O.SSOOOE-t-OZ
0.38000E*Q2
003eOOOE+02
O.S6000E+02
0.38000E+02
O.S6000E-1-02
0.38000E+02
0,36000E*02
0,3aOOOE*02

0.0
0.0
0.0
0.0
0.0
0.0
0.0
0,0
0.0
0.0
0.0
0  AREA SOURCES.
                  11 POINT SOURCES.
                           Figure  2  (continued)

-------
AREA
        COM VERSION 74114,  RUN    4
        (MICROGRAHS PER CUBIC METER)
               POINT           TOTAL
                                             CALIBRATED
COORDINATES
86.00
88. 00
86.00
68.00
ee.oo
86.00
88.00
68.00
89.00
89.00
89.00
89.00
89.00
89.00
89.00
89.00
69.00
89.00
90.00
90.00
90.00
90.00
90.00
90.00
90.00
90.00
90.00
90.00
91.00
91.00
91.00
91.00
91.00
91.00
91.00
91.00
91.00
91.00
92.00
92.00
92.00
92.00
92.00
92.00
92.00
92.00
92.00
92.00
93.00
93.00
87.00
81.00
89.00
90.00
91.00
92.00
93.00
9H. 00
87.00
86.00
89.00
90.00
91.00
92.00
93.00
9*. 00
95.00
96.00
87.00
88.00
89.00
90.00
91.00
92.00
93.00
9i|.00
95.00
96.00
87.00
88.00
89.00
90.00
91.00
92.00
93.00
911.00
95.00
96.00
87.00
86.00
89.00
90.00
91.00
92.00
93.00
94.00
95.00
96.00
87.00
66.00
F 1
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
P 2
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
F 1
169.
125.
336.
370.
376.
496.
415.
t09.
220.
258.
326.
481.
586.
876.
734.
653.
"•98.
397.
339.
367.
474.
731.
1074.
262.
1572.
900.
647.
5*7.
301.
317.
380.
625.
SHI.
635.
522.
465.
424.
341.
376.
457.
499.
610.
659.
729.
660.
521.
444.
370.
421.
556.
P 2
11.
a.
19.
19.
19.
18.
17.
17.
13.
14.
15.
22.
20.
20.
19.
24.
22.
20.
19.
17.
18.
27.
22.
18.
27.
28.
26.
28.
18.
17.
18.
28.
24.
23.
26.
25.
27.
24.
20.
21.
19.
29.
25.
31.
36.
32.
29.
25.
20.
20.
F 1
189.
125.
336.
370.
376.
496.
415.
409.
220.
258.
326.
481.
586.
676.
734.
653.
498.
397.
339.
367.
476.
731.
1074.
262.
1572.
900.
647.
547.
301.
317.
380.
625.
541.
635.
522.
465.
424.
341.
376.
457.
499.
610.
659.
729.
680.
521.
444.
370.
421.
558.
F 2
11.
8.
19.
19.
19.
18.
17.
17.
13.
14.
15.
22.
20.
20.
19.
24.
22.
20.
19.
17.
18.
27.
22.
18.
27.
28.
26.
28.
IB.
17.
18.
28.
24.
23.
26.
25.
27.
24.
20.
21.
19.
29.
25.
31.
36.
32.
29.
25.
20.
20.
P 1
189.
125.
336.
370.
376.
496.
415.
409.
220.
256.
326.
481.
586.
876.
734.
653.
498.
397.
339.
367.
476.
731.
1074.
262.
1572.
900.
647.
547.
301.
317.
380.
625.
541.
635.
522.
465.
424.
341.
376.
457.
499.
810.
659.
729.
660.
521.
11*4.
370.
421.
558.
P 2
11.
8.
19.
19.
19.
18.
17.
17.
13.
14.
15.
22.
20.
20.
19.
24.
22.
20.
19.
17.
18.
27.
22.
18.
27.
28.
26.
28.
18.
17,
18.
28.
24.
23.
26.
25.
27.
24.
20.
21.
19.
29.
25.
31.
36.
32.
29.
25.
20.
20.
f 1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
f 2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
1
1
1
0
0
1
1
                                                       (continued)
         Figure 3.   Output  c.ata.

-------
                                     COM VERSION! 74114,  RUN    4
                                     (MICROGRAHS PER CUBIC METER)
                                           POINT          TOTAL
                                                                     CALIBRATED
M
COORDINATES
93.00
93.00
93.00
93.00
93.00
9S.OO
93.00
93.00
94,00
94,00
94.00
94.00
94.00
94.00
94.00
9"*. 00
94.00
91.00
94,00
94.00
95,00
95.00
95.00
95.50
95.00
95.50
95,50
95.00
95,50
95.00
95.00
95.00
95.00
96.00
96.00
96.00
96.50
96.00
96.50
96.50
96.00
96.50
96.00
96.00
96.00
97.00
97.00
97.00
97.00
97.00
89.00
90.00
91,00
92.00
93.00
9IJ.OO
95.00
96.00
85.00
66.00
87.00
68.00
69.00
90.00
91.00
92,00
93.00
94.00
95.00
96,00
87.00
66.00
89.00
89.50
90.00
90.00
90.50
91.00
91.00
92.00
93.00
94.00
96.00
87.00
86.00
89.00
69.50
90.00
90.00
90.50
91,00
91,50
92.00
93.00
94.00
87.00
68.00
89.00
90.00
91.00
F 1
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0,
0.
0,
0.
0.
0.
0.
0.
0.
0,
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0,
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
P 2
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
o.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0,
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0,
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
F 1
853.
1570.
1281.
1053.
741.
559.
454.
445.
354.
462.
617.
939.
1810.
197.
2908.
1523,
1013.
729.
560.
444.
315.
462.
507,
600.
989.
1129.
873.
637.
743.
571.
383.
284.
465.
336.
359.
575.
287.
300.
541.
344.
905.
277.
512,
419.
301.
153.
171.
179.
341.
226.
P 2
17.
24.
24.
36.
36.
33,
29.
33,
24.
28.
29.
27.
14.
1.
27.
47,
48.
44.
36.
33.
13,
14.
7.
7.
12.
IS.
11.
11.
12.
13*
14.
12,
32.
13,
6.
7.
7.
13.
13,
10.
11.
10.
10.
13,
11.
7.
6.
6.
12.
9.
F 1
853.
1570.
1281.
1053.
741.
559.
454.
445.
354.
462.
&17.
939.
1610.
197.
2906.
1523.
1013.
729,
560.
444.
315.
462.
507.
600.
969,
1129,
873.
637.
743.
571.
333.
284.
465.
336.
359,
575.
287.
300.
541,
344.
905.
277,
512.
419,
301.
153.
171.
179.
341,
226.
f 2
17.
24.
24.
36.
36.
33.
29.
33.
24.
28.
29.
27.
14.
1.
27.
47.
t8.
44.
38.
33,
13.
14,
7.
7,
12,
13,
11.
11.
12.
15.
14.
12.
32.
13.
8.
7.
7.
13.
IS.
10.
11.
10.
10.
13.
11.
7.
6.
6.
12.
9.
F1 1
853.
1570.
1281.
1053.
741.
559.
454.
445.
354.
462.
617.
939.
1810.
197.
2908.
1923.
1013.
729,
560.
444,
315.
462.
507.
600.
969,
1129.
873,
637.
743.
571.
383.
284.
465,
336.
359.
575.
287.
300.
541.
344.
905.
277.
512.
419.
301.
153.
171.
179.
341,
228.
P 2
17.
24.
24.
36.
36.
33.
29.
33.
24.
28.
29.
27.
14.
1.
27.
47.
48.
44.
38.
33.
13.
14.
7,
7.
12.
13.
11,
11.
12.
15.
14,
12.
32.
13,
6,
7.
7.
13.
13.
10.
11.
10.
10,
13.
11.
7.
6.
6.
12.
9.
F 1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
F 2
1
1
1
1
1
0
0
0
0
0
1
1
1
1
1
1
1
0
0
0
1
1
1
0
1
0
0
1
0
1
1
1
0
1
1
1
0
1
0
0
1
0
1
1
1
1
1
1
1
1
                                                                               (continued)
                                      Figure  3  (continued)

-------
COM VERSION 74114i RUN *
(MICROGRAHS PER CUBIC HETERI


COORDINATES
97.00
97.00
97.00
98.00
98.00
98.00
98,00
98.00
98.00
98.00
98.00
99.00
99.00
99.00
100.00
100.-00
100,00
101.00
101.00
101.00
92.00
93.00
94.00
87.00
88.00
69.00
90.00
91.00
92.00
93.00
94.00
89.00
90.00
91.00
89.00
90.00
91.00
89.00
90.00
91.00
AREA
P 1
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
P 2
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
POINT
F 1
207.
165.
126.
125.
lot.
111.
204.
154.
155.
137.
107.
83.
144.
114.
96.
110.
109.
77.
94.
88.
P 2
9.
8.
7.
6.
5.
5.
10.
8.
7.
7.
6.
5.
8.
6.
7.
7.
7.
6.
6.
6.
TOTAL
F 1
207.
165.
126.
125.
104.
111.
204.
154.
135.
137.
107.
83.
144.
114.
96.
110.
109.
77.
94.
88.
P 2
9.
8.
7.
6.
5.
5.
10.
8.
7.
7.
6.
5.
8.
6.
7.
7.
7.
6.
6.
6.
CALIBRATED
f 1
207.
165.
126.
125.
104.
111.
204.
154.
135.
137.
107.
83.
144.
114.
96.
110.
109.
T7.
94.
88.
P 2
9.
8.
7.
6.
5.
5.
10.
8.
7.
7.
6.
5.
8.
6.
7.
7.
7.
6.
6.
6.
OBSERVED
P 1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
P 2
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
LO
                                      Figure 3  (continued)

-------
as a fraction of the average total for a year.  The compass is
divided into 16 sectors beginning with 1 for north by northeast
around to 16 for north.  The source input X and Y coordinate
parameters are taken from topographic maps and are in kilometers.
SI and S2 are point source emission rates for ethylene dichlo-
ride and vinyl chloride, respectively.  SH is stack height in
meters, D is stack diameter in meters, VS is exit velocity of the
effluent, and T is average ambient temperature in degrees
centigrade.

The output data show the ground-level concentrations of ethylene
dichloride and vinyl chloride respectively, as PI and P2.  The
X and Y coordinates correspond to those in the input.  Any number
of receptor locations  (points where a computed concentration is
requested) may be used.  The output coordinates have been used to
plot the isopleth in Figure 1 for ethylene dichloride.

Two variables unknown at the time if isopleth generation for
these sources were the temperature of the gases leaving the
stacks and the exit velocity of these gases.  A comparison of
isopleths generated at 38°C and 300°C showed the location of
maximum concentration at the same point, but the 500-yg/m3 iso-
pleth shifted outward by about half a kilometer at the higher
temperature.  Discussions with plant personnel in the Houston
area indicated that scrubbers are used in most of the plant,
which would suggest that the lower temperature is more realistic.
Different exit velocities were used to determine that the model
is not sensitive to this input.

At this point, a tape of the recently improved COM computer pro-
gram was received; it was utilized in the rest of this study.

The rest of the input data for Houston were gathered for all of
the probable carcinogens indicated, and the computerized CDM was
run.  The results were plotted and a three-dimensional model was
assembled.  The results are shown in Figure 4.  Three different
locations were found to have similar, high concentrations of
carcinogens.  These areas were located on a map of Houston as
shown in Figure 5.

At the three points of maximum carcinogen concentration, the
composition and concentration of each component carcinogenic
chemical was determined.  Results are displayed in Table 18.
These are the prime locations to be sampled in the third phase
of this contract and contract 68-02-2774  (portable carcinogen
tester).

Similar data are being generated for the other cities of
interest.
                                44

-------
    Figure 4.  Houston carcinogen isopleth.
TABLE 18.  AVERAGE CONCENTRATIONS AT POINTS OF
           MAXIMUM POLLUTION IN HOUSTON
         [Micrograms per cubic meter]

Compound
Acrylonitrile
Benzene
Carbon tetrachloride
Chloroform
Dichlorobutene
Ethylene dichloride
Tetrachloroe thane
Epichlorohydrin
Trichloroethylene
Vinyl chloride
Vinilydene chloride
Ethylene dibromide
82,88
1.0
1,366.0
6.0
2.0
1.0
26.0
0.009
0.15
5.0
7.0
0.004
0.14
90,92
0.1
6.0
190.0
92.0
0.02
977.0
0.022
1.0
12.0
15.0
0.165
0.01
95,90
0.1
5.0
251.0
123.0
0.02
757.0
0.018
1.0
10.0
2.0
0.220
0.10
                      45

-------
Figure 5.   Locations of maximum concentration of
           pollutants in Houston.
                        46

-------
                           REFERENCES
 1.   Eimutis,  E.  C. ,  and R.  P.  Quill.   Source Assessment:   Non-
     criteria  Pollutant Emissions.   EPA-600/2-77-107e (National
     Technical Information Service  No.  PB 270 550),  1977.

 2.   Suspected Carcinogens - A Subfile  of the NIOSH  Toxic  Sub-
     stances List,  1976 Edition,  H. E.  Christensen,  ed.   Publica-
     tion No.  (NIOSH)  75-188, U.S.  Department of Health,
     Education,  and Welfare, National  Institute for  Occupational
     Safety and Health.

 3.   Registry  of Toxic Effects of Chemical Substances,  Volumes I
     and II, E.  J.  Fairchild, ed.  DHEW Publication  No.  (NIOSH)
     78-104-A, U.S.  Department of Health, Education, and  Welfare,
     National  Institute for Occupational Safety and  Health,
     September 1977.

 4.   Sawicki,  E.  Chemical Composition  and Potential "Genotoxic"
     Aspects of Polluted Atmospheres.   In:  Air Pollution and
     Cancer in Man,  U. Mohr, D. Schmahl, and L. Tomatis,  eds.
     International Agency for Research  on Cancer Scientific Pub-
     lication No. 16, 1977.   pp.  127-157.

 5.   Survey of Compounds Which Have Been Tested for  Carcinogenic
     Activity, Volumes 1 through 7.  DHEW Publication No.   (NIH)
     75, Public Health Service Publication No. 149,  U.S.  Depart-
     ment of Health,  Education, and Welfare, National Institutes
     of Health.

 6.   Fuller, B., et al.  Preliminary Scoring of Selected Organic
     Air Pollutants.   National Technical Information Service Nos.
     PB 264 442 through PB  264 446, 1976.

 7.   Brown, S. L.,  et al.  Research Program on Hazard Priority
     Ranking of Manufactured Chemicals.  National Technical In-
     formation Service No. PB 263 161,  1975.

 8.   Radding,  S. B.,  et al.   Review of  the Environmental Fate  of
     Selected Chemicals.  EPA-560/5-77-003  (National Technical
     Information Service No. PB 267 121), May 1977.

 9.   Mutation Research, 57:11-15, 1978.

10.   Journal of Agricultural and Food Chemistry, 24:560,  1976.


                                 47

-------
11.   Biochemical Pharmacology,  26(8) :729-734 ,  1977.

12.   Mutation Research,  31:268-269, 1975.

13.   Mutation Research,  40(2):73-83,  1976.

14.   Mutation Research,  40(3):273-275,  1976.

15.   Cancer Research, 34:2576,  1974.

16.   Proceedings of the National Academy of Sciences of the
     United States, 72 ( 6) :2423-2427,  1975.

17.   International Agency for Research on Cancer Scientific Pub-
     lication No. 12, 1976.   pp. 61,  125, and 623.

18.   International Agency for Research on Cancer Scientific Pub-
     lication No. 10, 1974.   pp. 161-181.

19.   Seasonal & Annual (Day/Night)  Wind Distribution by Pasquill
     Stability Classes (6),  STAR Program.  U.S. Department of
     Commerce, National Oceanic and Atmospheric Administration,
     Environmental Data Service, National Climatic Center, Ashe-
     ville, North Carolina,  July 15,  1977.

20.   Holzworth, G. C.  Estimates of Mean Maximum Mixing Depths
     in the Contiguous United States.  Monthly Weather Review,
     92 (5) :235-242, 1964.

21.   Statistical Abstract of the United States, 97th Edition.
     U.S.  Bureau of the Census, Washington, D.C.,  1976.  p. 191.

22.   Khan, Z. S., and T. W.  Hughes.  Source Assessment:  Poly-
     vinyl Chloride.  EPA-600/2-78-004i, U.S. Environmental
     Protection Agency, Cincinnati, Ohio, May 1978.  105 pp.

23.   Scientific and Technical Assessment Report on Vinyl Chloride
     and Polyvinyl Chloride.  EPA-600/6-75-004, U.S. Environmen-
     tal Protection Agency,  Washington, D.C., December 1975.
     130 pp.

24.   Busse, A. D., and J. R. Zimmerman.  User's Guide for the
     Climatological Dispersion Model.  EPA-R4-73-024, U.S. Envi-
     ronmental Protection Agency, Research Triangle Park, North
     Carolina, December 1973.  144 pp.

25.   Davies, J. C.  Co-Carcinogenesis with Respect to the Con-
     tents of Cigarette Tobacco.  R. Soc. Health J., 93 (6):296-
     301,  1973.
                                 48

-------
26.   Hartwell, J. L.  Survey of Compounds Which Have Been Tested
     for Carcinogenic Activity, Second Edition.  National Tech-
     nical Information Service No. PB 216 478, 1951.

27.   Shabad, L. M., et al.  The Feasibility of Preventing the
     Effects of Carcinogens on Man.  Kazan Med. Zh,  (5):92-93,
     1973.

28.   Terrell, J. H., and I. Schmeltz.  Cigarettes:  Chemical
     Effect of Sodium Nitrate Content.  Science, 160:1456, 1968.

29.   Izard, C.  Mutagenic Effects of Acrolein and its Two Epox-
     ides, Glycidol, and Glycidal, in Saccharomyces Cerevisiae.
     C. R. Acad. Sci., Ser. D., 276 (23) : 3037-3040, 1973.

30.   Epstein, S. S., et al.  Detection of Chemical Mutagens by
     the Dominant Lethal Assay in the Mouse.  Toxicol. Appl.
     Pharmacol., 23:288-325, 1972.

31.   Bignami, M., et al.  Relationship Between Chemical Structure
     and Mutagenic  Activity in Some Pesticides:  The Use of
     Salmonella  Typhimurium and Aspevgillus Nidulans.  Mutat.
     Res., 46(3):243-244, 1977.

32.   Allport, J., et al.  A Study of Industrial Data on Candidate
     Chemicals for  Testing.  National Technical Information Ser-
     vice No. PB 274 264, 1977.

33.   Verschueren, K.  Handbook of Environmental Data on Organic
     Chemicals.  Van Nostrand Reinhold Co., New York, 1977.

34.   Milvey,  P-, and M. Wolff.  Mutagenic Studies with Acryloni-
     trile.   Mutat. Res., 48 (3-4) :271-278, 1977.

35.   Venitt,  S., et al.  Mutagenicity of Acrylonitrile  (Cyano-
     ethylene) in Escheriahia Coli.  Mutat.  Res.,  45:283-288,  1977.

36.   Acrylonitrile  Linked to Cancer in Workers.  Chem. Eng. News,
     55:6, 1977.

37.   Finklea, J. F.  Acrylonitrile.  Am.  Ind. Hyg. Assoc. J.,
     38:417-422, 1977.

38.   Song, J., and  W. E. Harville.  Carcinogenicity  of Aldrin
     and Dieldrin on Mouse and Rat Liver.  Fed. Proc.,  23:336,
     1964.

39.   Diechmann, W.  B., et al.  Tumorigenicity of Aldrin, Diel-
     drin, and Endrin in the Albino Rat.  Ind. Med.  Surg.,  39(10)
     426-434, 1950.
                                 49

-------
40.   Wurster,  C.  F.   Aldrin and Dieldrin.   Environment, 13(8):
     33-45,  1971.

41.   Epstein,  S.  S.   Prevention - Environmental Exposure:  An
     Overview, Including the Role of Pesticides.  Third Inter-
     national  Symposium on Detection and Prevention of Cancer,
     1976.   p. 5.

42.   Epstein,  S.  S.   Case Study 5:   Aldrin and Dieldrin Suspen-
     sion Based on Experimental Evidence and Evaluation and
     Societal  Needs.   Ann. N.Y. Acad.  Sci., 271:187-195, 1976.

43.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 5, 1974.   pp. 25-38.

44.   Brown,  S. L., et al.  Research Program on Hazard Priority
     Ranking of Manufactured Chemicals.   National Technical In-
     formation Service No. PB 263 164,  1975.

45.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 4, 1974.   pp. 27-36.

46.   Fluck,  E. R., et al.  Evaluation of a DNA Polymerase-
     Deficient Mutant of E. Coli for the Rapid Detection of
     Carcinogens.   Chem. Biol. Interact.,  15:219-231, 1976.

47.   Schmall,  D.   Prufung von Naphthalin und Anthracen auf Car-
     cerogene Wirking an Ratten.  Zeitschrift fur Krebsforschung,
     60:697-710,  1955.

48.   Stanton,  M.  F.,  et al.  J. Natl.  Cancer Institute, 49(3):
     867-877,  1972.

49.   Pienta, R. J.,  et al.  Morophological Transformation of
     Early Passage Golden Syrian Hamster Embryo Cells Derived
     from Cryopreserved Primary Cultures as a Reliable -in Vitro
     Bioassay for Identifying Diverse Carcinogens.  Int. J.
     Cancer, 19:642-655, 1977.

50.   DiPaolo,  J.  A.,  et al.  Qualtitation of Chemically Induced
     Neoplastic Transformation of BALB/3T3 Cloned Cell Lines.
     Cancer Research, 32:2686-2695, 1972.

51.   Purchase, I.  F.  H., et al.  Evaluation of Six Short-Term
     Tests for Detecting Organic Chemical Carcinogens and Recom-
     mendations for Their Use.  Nature,  264:624-627, 1976.

52.   McCann, J.,  et al.  Detection of Carcinogens as Mutagens in
     the Salmonella/Microsoiae Test, Assay of 300 Chemicals.
     Proc.  Natl.  Acad. Sci.  (USA), 72:5135-5139, 1975.
                                 50

-------
53.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 3, 1973.  pp. 45-68.

54.   TLVs® Threshold Limit Values for Chemical Substances and
     Physical Agents in the Workroon Environment with Intended
     Changes for 1977.  American Conference of Governmental
     Industrial Hygienists, 1977.

55.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 7, 1974.  pp. 203-222.

56.   Brown, S. L., et al.   Research Program on Hazard Priority
     Ranking of Manufactured Chemicals.  National Technical In-
     formation Service No. PB 263 162, 1975.

57.   Walker, P.  Air Pollution Assessment of Benzene.  National
     Technical Information Service No. PB 256 734, 1976.

58.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 1, 1972.  pp. 80-86.

59.   Vesselinovitch, S. D., et al.  Factors Modulating Benzidine
     Carcinogenicity Bioassay.  Cancer Res., 35 (10) :2814-2819,
     1975.

60.   Brown, S. L., et al.   Research Program on Hazard Priority
     Ranking of Manufactured Chemicals.  National Technical In-
     formation Service No. PB 263 163, 1975.

61.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 3, 1973.  pp. 91-136.

62.   Takizawa, N.  On the Carcinogenic Action of Certain Quinones
     Proc. Imperial Acad.    (Tokyo), 16:309-312, 1940.

63.   Tiedmann, H.  Ztschr. Naturforsch., 8b:49-50, 1953.

64.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 15, 1977.  pp. 255-264.

65.   Vogel, E.  Differential Sensitivity of Immature and Mature
     Oocytes of Drosophila Melanogaster to the Induction of
     Dominant Lethals Following Treatment of Mono- and Polyfunc-
     tional Aziridine Analogues.  Mutat. Res., 14:250-253, 1972.

66.   Lueers, H., and G. Obe.  Possible Mutagenic Activity of
     p-Benzoquinone.  Mutat. Res., 15:77-80, 1972.

67.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 11, 1976.
                                51

-------
68.  McCann, J., et al.   Detection of Carcinogens as Mutagens:
     Bacterial Tester Strains with R Factor Plasmids.  Proc. Nat.
     Acad. Sci  (USA), 72:979-983, 1975.

69.  Evaluation of Carcinogenic, Teratogenic, and Mutagenic
     Activities of Selected Pesticides and Industrial Chemicals,
     Volume I.  National Technical Information Service No. PB 223
     159, 1968.

70.  IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 4, 1974.  pp. 231-238.

71.  Smith, A. H., and L. Ellis.  Styrene Butadiene Rubber Syn-
     thetic Plants and Leukemia  (Letter to Editor).  J. Occup.
     Med., 19(7):441, 1977.

72.  DiVito, G., and G.  L. Sommi.  The Incidence of Infectious
     Diseases, Hemopathies, and Neoplasms in Workers Exposed to
     Carbon Disulfide.  Folia Med. (Napoli), 46(11):972-979, 1963.

73.  IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 1, 1972.  pp. 53-60.

74.  Johns, R.  Air Pollution Assessment of Carbon Tetrachloride.
     National Technical Information Service No. PB  256 732, 1976.

75.  Fishbein, L.   Industrial Mutagens and Potential Mutagens, I.
     Halogenated Aliphatic Derivatives.   Mutat. Res., 32:267-308,
     19 7 6.

76.  Fuhrman, F. A., et al.  Arch. Inst. Pharmacodym., 102:113-
     125, 1955.

77.  Innes, J. R.  M., et al.  J. Nat. Cancer Inst., 42:1101-1114,
     1969.

78.  Elmore, J. D., et al.  Vinyl Chloride Mutagenicity via the
     Metabolites Chlorooxirane and Chloracetaldehyde Monomer
     Hydrate.  Biochem.  Biophys. Acta, 442:409-419, 1976.

79.  Rannug, U., et al.   The Mutagenicity of Chloroethylene
     Oxide, Chloroacetaldehyde,  2-Chloroethanol and Chloroacetic
     Acid, Conceivable Metabolites of Vinyl Chloride.  Chem.
     Biol. Interact., 12(3-4):251-263, 1976.

80.  Bartsch, H.,  et al.  Human, Rat and Mouse-Liver Mediated
     Mutagenicity of Vinyl Chloride in S. Typhimur-ium Strains.
     Int. J. Cancer, 15 (3) : 429-437, 1975.

81.  Malaveille, C., et al.  Mutagenicity of Vinyl Chloride,
     Chloroethyleneoxide, Chloroacetaldehyde and Chloroethanol.
     Biochem. Biophys. Res. Comm., 63 (2) :363-370, 1975.


                                 52

-------
82.   Bioassay of Chlordane for Possible Carcinogenicity  (CAS No.
     57-74-9).   National Technical Information Service No. PB 271
     977.

83.   Bakke, 0.  M.,  and T. Midtvedt.  Influence of Germ-Free Status
     on the Excretion of Simple Phenols of Possible Significance
     in Tumor Promotion.  Experimentia, 26 (5):519, 1970.

84.   Bock, F. G., et al.  Composition Studies on Tobacco.  XLIV.
     Tumor-Promoting Activity of Subfractions of the Weak Acid
     Fraction of Cigarette Smoking Condensate.  J. Nat. Cancer
     Inst., 47 (2):429-436, 1971.

85.   Shustova,  M. N., and L. N. Samiolovich.  Blastomogenicity of
     Neutralized Soots from the Sulfate Shop of a Coke Plant.
     Gig.  Sanit., 36 (7) :103-104, 1971.

86.   Bone, E. S., et al.  The Production of Urinary Phenols by
     Human Gut Bacteria,  (Meeting Abstract).  J. Med. Microbiol.,
     9(2):vi, 1976.

87.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 5, 1974.  pp. 75-81.

88.   Jurek, A.  Carcinogenicity of Pesticides.  Roczn. Panstw.
     Zakl. Hig., 25 (5):563-576, 1974.

89.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 1, 1972.  pp. 61-65.

90.   Powers, M. B., and R. W. Yoelker.  Evaluation of the Onco-
     genic Potential of Chloroform by Long-Term Oral Administra-
     tion in Rodents  (Meeting Abstract).  Toxicol. Appl. Pharmacol.,
     37:179, 1976.

91.   Renne, R. A., et al.  Pathology of Long-Term Oral Adminis-
     tration of Chloroform in Rodents  (Meeting Abstract).  Toxo-
     col.  Appl. Pharmacol., 37:179-180, 1976.

92.   Chloroform Tagged as Carcinogen in Mice.  Chem. Eng. News,
     54:6, 1976.

93.   Khachatryan, E. A.  The Role of Chloroprene in the Process
     of Skin Neoplasm Formation.  Gig. Tr. Prof. Zabol.,  16:54-
     55, 1972.

94.   Khachatryan, E. A.  The Occurrence of Lung Cancer Among
     People Working with Chloroprene.  Problems in Oncology,
     18:85, 1972.

95.   Khachatryan, E. A.  Lung Cancer Incidence Among Chloroprene
     Handling Workers.  Yopr. Onkol., 18:85-86, 1972.


                                53

-------
 96.   Casto,  B.  C.,  et al.   Assay of Industrial Chemicals in
      Syrian Hamster Cells  for Enhancement of Viral Transformation.
      Proc.  Am.  Assoc. Cancer Res.,  18:155, 1977.

 97.   Bartsch,  H.,  et al.   The Predictive Value of Tissues-Mediated
      Mutagenicity  Assays  to Assess  the Carcinogenic Risk of Chem-
      icals.   IARC  Sci. Pub. No. 12, 1976.  pp. 467-491.

 98.   Zilfyan,  V. N., et al.  Experimental Study of Chloroprene
      for Carcinogenicity.   Yopr. Onkol., 23:61-65, 1977.

 99.   Zilfyan,  V. N., et al.  Results of a Study of Chloroprene
      for Carcinogenicity.   Zh. Eksp. Klin. Med., 15:54-57, 1975.

100.   Lloyd, J.  W.   Cancer  Risks Among Workers Exposed to Chloro-
      prene.  Ann.  N.Y. Acad. Sci.,  271:91-93, 1976.

101.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to  Man, Volume 3, 1973.  pp. 159-177.

102.   Epstein,  S.  S., and  H. Shafner.  Chemical Mutagens in the
      Human Environment.  Nature, 219:385-387, 1968.

103.   Radiation Research,  Supplement 3:193, 1963 (as cited in
      Reference 2).

104.   J. Nat. Cancer Inst., 37:825,  1966  (as cited in Reference 2).

105.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to  Man, Volume 5, 1974.  pp. 83-124.

106.   Vogel, E.   The Relation Between Mutational Pattern and
      Concentration by Chemical Mutagens in Dvosophila.  IARC
      Sci. Pub.  No.  12, 1976.  pp. 117-137.

107.   Kotin, P., and H. L.  Falk.  Radiation Research Supplement
      3:193-211, 1963  (as  cited in Reference 5).

108.   Saffioti,  U.,  and P.  Shubik.  Nat. Cancer Inst. Monog.,
      10:489-507,  1963  (as  cited in Reference  5).

109.   Hoshing,  H.,  et al.   Gann 61(2):121-124, 1970  (as cited in
      Reference 5).

110.   Van Duuren,  B. L. , et al.  J.  Nat. Cancer Inst., 39:1217-
      1228,  1967 (as cited  in Reference  5).

111.   Documentation of the  Threshold Limit Values for Substances
      in Workroom Air.  American Conference of Governmental In-
      dustrial  Hygienists,  1976.  pp. 96-97.
                                54

-------
112.   Shubik,  P., et al.  Survey of Compounds Which Have Been
      Tested for Carcinogenic Activity, Supplement I.  National
      Technical Information Service No. PB 216 248, 1957.

113.   Singh, A. R.,  et al.  Mutagenic and Antifertility Sensitiv-
      ities of Mice to Di-2-ethylhexyl Phthalate  (DEHP) and
      Dimethoxyethyl Phthalate  (DMEP).  Toxicol. Appl. Pharmacol.,
      29(1) :35-46, 1974.

114.   Mathur,  S. P.   Respirometric Evidence of the Utilization of
      Dioctyl and Di-2-ethylhexyl Phthalate Plasticizers.  J.
      Environ. Qual., 3(3) :207-209 , 1974.

115.   Peakall, D. B.  Phthalate Esters:  Occurrence and Biological
      Effects.  Residue Reviews, 54:1-41, 1975  (177 references).

116.   Recent Progress in Safety Evaluation Studies on Plasticizers
      and Plastics and Their Controlled Use in Japan.  Environ.
      Health Perspec., 17:203-209, 1976.

117.   Singh, A. R., et al.  Mutagenic and Antifertility Sensi-
      tivities of Mice to Phthalic-Acid Esters.  J. Anim. Sci.,
      38(1):216,  1974.

118.   Taylor, B. F., and E. F.  Corcoran.  Biodegradation of
      Phthalic Acids and Esters.  Contract ES-00994-02, National
      Institute of Environmental Health Sciences,  1975.

119.   Autain, J.  Toxicity and  Health Threats of Phthalate Esters,
      Review of the Literature.  Environ. Health Perspec., 4:3-26,
      1973.

120.   Yagi, Y., et al.  Teratogenicity and Mutagenicity of a
      Phthalate Ester.  Teratology, 14:259-260, 1976.

121.   Dillingham, E. 0., and J. Autain.  Teratogenicity, Muta-
      genicity and Cellular Toxicity of Phthalate  Esters.  Environ.
      Health Perspec. 3:81-89,  1973.

122.   Landon, J.  C.  Carcinogenesis Bioassay of Di(2-ethylhexyl)
      Phthalate.  National Cancer Institute contract with Tracer
      Jitco, Inc., 10/76-9/77,  1977.

123.   Saeger, V. W., and E. S.  Tucker.  Biodegradation of Phthalic
      Acid  Esters in River Water and Activated  Sludges.  Appl.
      Environ. Microbiol., 31(1):29-34, 1976.

124.   Palmer, K. A., et al.  The Mutagenic Assay  of  Some Hair  Dye
      Components  Using  the Thymidine Kinane Locus  of L51178Y Mouse
      Lymphoma Cells  (Meeting Abstract).  Toxicol. Appl. Pharmacol
      37(1) :108,  1976.
                                 55

-------
125.   Kinkel,  H.  J.,  and S.  Holzmann.   Study of Long-Term Percuta-
      neous Toxicity  and Carcinogenicity of Hair Dyes (Oxidizing
      Dyes)  in Rats.   Food Cosmet.  Toxicol., 11(4):641-648, 1973.

126.   Burnett, C.,  et al.   Long-Term Toxicity Studies on Oxida-
      tion Hair Dyes.  Food Cosmet.  Toxicol., 13 (3) :353-357, 1975.

127.   Burnett, C.,  et al.   Dominant Lethal Mutagenicity Study on
      Hair Dyes.   J.  Toxicol.  Environ.  Health, 2(3) :657-662, 1977.

128.   Dybing,  E., and S. S.  Thorgeirsson.   Metabolic Activation
      of 2,3-Diaminoanisole, a Hair-Dye Component.  Biochem.
      Pharmacol., 26(8):729-734,  1977.

129.   Dybing,  E., and T. Aune.  Hexachlorobenzene Induction of
      2,4-Diaminanisole Mutagenicity in Vitro.   Acta Pharmacol.
      Toxicol., 40(5):575-583, 1977 (24 references).

130.   Ames. B. N.,  et al.   Hair Dyes are Mutagenic;  Identifica-
      tion of a Variety of Mutagenic Ingredients.   Proc. Natl.
      Acad. Sci.  (USA)  72 (6) : 2423-2427 , 1975.

131.   Blijleven,  W. G.   Mutagenicity of Four Hair Dyes in Drosph-
      ila Melanogaster.   Mutat.  Res., 48(2):181-185 ,  1977.

132.   Health Hazards; 2,4-Diaminoanisole.   Occupational Safety &
      Health Reporter,  7(35):1331,  1978.

133.   2,4-Diaminoanisole  (4-Methoxy-m-phenylenediamine)  in Hair
      and Fur Dyes.  Current Intelligence Bulletin 19, January 13,
      1978.

134.   Kimbrough,  R. D., and T. B. Gaines.   Effect of Organic Phos-
      phorous Compounds and Alkylating  Agents on the Rat Fetus.
      Arch. Environ.  Health, 16:805-808, 1968.

135.   Trinh-Van-Bao,  et al.  Chromosome Aberrations in Patients
      Suffering Acute Organic Phosphate Insecticide Intoxication.
      Humangenetik,  24:33-57,  1974.

136.   Tzoneva-Maneva, M. T., et al.  Influence of Diazinon and
      Lindane on the  Mitotic Activity and the Caryotype of Human
      Lymphocytes,  Cultivated in Vitro.  Bibl. Haematol. (Base 1),
      38(1) :344-347,  1971.

137.   Marshall, T.  C.,  et al.   Screening of Pesticides for Muta-
      genic Potential Using Salmonella  Typhimurium Mutants.
      J. Agric. Food  Chem., 24:560-563, 1976.

138.   Mohn, G.  5-Methyltryptophan Resistance Mutations in Escher-
      icnia Coli  K-12.   Mutat. Res., 20(1):7-15, 1973.
                                56

-------
139.   Ashwood-Smith, M. J.,  et al.  Mutagenicity of Dichlorvos.
      Nature, 240:418-419, 1972.

140.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 7, 1974.  pp. 231-244.

141.   Guerin, M.,  et al.  Inhibitory Action of Chemical Carcino-
      gens on Mitosis of Rat Lung Cell Cultures; 2.  Comparative
      Study of Carcinogenic and Noncarcinogenic Substances.
      C. R. Soc. Biol., 165:2255-2258, 1971.

142.   Prasad, I.  Mutagenic Effects of the Herbicide 3',4'-Di-
      chloro-propionanilide and Its Degradation Products.  Can.
      J. Microbiol., 16:369-372,  1970.

143.   Prasad, I.,  and D. Pramer.  Mutagenic Activity of Some
      Chloroanilines and Chlorobenzenes.  Genetics, 60:212-213,
      1968.

144.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 4, 1974.  pp. 49-55.

145.   Stula, E. F., et  al.  Experimental Neoplasia in Rats from
      Oral Administration of 3,3-Dichlorobenzidine, 4,4'-Methyl-
      enebis(2-chloroaniline), and 4,4'-Methylenebis(2-methylani-
      line) .  Toxicol.  Appl. Pharmacol., 31(1) :159-176, 1975.

146.   Bartsch, H., et  al.  Alkylating and Mutagenic Metabolites
      of Halogenated Olefins Produced by Human and Animal Tissues.
      Proc. Am. Assoc.  Cancer  Res.,  17:17,  1976.

147.   Van Duuren, B. L.,  et al.   Carcinogenic Activity of Di-  and
      Tri-functional a-Chloro  Ethers and of 1,4-Dichlorobutene-2
      in ICR/HA Swiss Mice.  Cancer  Res., 35:2553-2557, 1975.

148.   Andrews, A. W.,  et  al.   The Identification of Endogeneous
      and Exogeneous Mutagenic Compounds.   4th Carcinogenesis
      Bioassay Program, Orlando,  Florida, February 1976.

149.   Stevens, S., et  al.  Phenotypic and Genetic Effects in
      Neurospora Crassa Produced  by  Selected Gases and Gases
      Mixed with Oxygen.  Develop. Ind. Microbiol.,  12:346-353,
      1971.

150.   Schwetz, B. A.,  et  al.   Embryo- and Fetotoxicity of Inhaled
      Carbon Tetrachloride, 1,1-Dichloroethane, and Methyl Ethyl
      Ketone in Rats.   Toxicol. Appl. Pharmacol.,  28:452-464,
      1974.

151.   National Cancer  Institute Draft Summaries of Bioassay  Re-
      ports, 1,1-Dichloroethane.  Chem. Reg.  Rep., 1(45):1597-
      1598,  1978.


                                 57

-------
152.   Anderson,  K.  J.,  et al.   Evaluation of Herbicides for Possi-
      ble Mutagenic Properties.   J.  Agr. Food Chem.,  20:649-656,
      1972.

153.   Boutwell,  R.  K.,  and D.  K.  Bosch.   The Tumor-Promoting
      Action of  Phenol  and Related Compounds for Mouse Skin.
      Cancer Res.,  19:413-424, 1959.

154.   Torkelson, T. R.,  and F. Oyen.  The Toxicity of 1,3-Dichlo-
      ropropene  as  Determined by Repeated Exposure of Laboratory
      Animals.  Am. Indust. Hyg.  Assoc.  J.,  38(5):217, 1977.

155.   DeLorenzo, F., et al.  Mutagenicity of Pesticides Contain-
      ing 1,3-Dichloropropene.  Cancer Res., 37 ( 6) :1915-1917, 1977.

156.   Neudecher, T., et al.  In Vitro Mutagenicity of the Soil
      Nematicide 1,3-Dichloropropene.  Experientia, 33(8):1084-
      1085,  1977.

157.   Shirasu, Y.,  et al.  Mutagenicity Screening of Pesticides
      in the Microbial  System.  Mutat. Res., 40:19-30, 1976.

158.   Bioassay of Dichlorvos for Possible Carcinogenicity, CAS
      No. 62-73-7.   National Technical Information Service No.
      PB 270 937, 1977.

159.   Rieger, M. M.  Cosmetic Science:  1975 Literature Survey.
      Cosmet. Perfum.,  91(4):25-36,  1976.

160.   Hadidian,  Z., et  al.  J. Nat.  Cancer Inst., 41 (4) :985-1036,
      1968.

161.   Dushutin,  K.  K.,  and E.  D.  Sopach.  The Role of the Reaction
      of Dimethylamine  with Nitrogen Tetroxide and Ozone in Atmos-
      pheric Pollution.   Gig.  Sanit., 7:14-18, 1976.

162.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals  to  Man,  Volume 4, 1974.   pp. 137-143.

163.   Wilson, R. B.  Species Variation in Response to Dimethyl-
      hydrazine.  Toxicol. Appl.  Pharmacol., 38 (3) : 647-650, 1976.

164.   National Cancer Institute Draft Summaries of Bioassay
      Reports, 2,4-Dinitrotoluene.  Chem. Reg. Rep.,  1(45):1598,
      1978.

165.   Kociba, R. J., et al.  1,4-Dioxane:  Correlation of the
      Results of Chronic Ingestion and Inhalation Studies with
      its Dose-Dependent Fate in Rats.  Aerosp. Med.  Res. Lab.
      (Tech. Rep.)  AMRL-TR-125, 1975.  pp. 345-354.
                                58

-------
166.   Argus, M. F., et al.  Dose-Response and Ultrastructural
      Alternatives in Dioxane Carcinogenesis.  Eur. J. Cancer,
      9 (4) :237-243, 1973.

167.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 11, 1976.  pp. 247-256.

168.   Torkelson, T. R., et al.  1,4-Dioxane.  II.  2-Year Inhala-
      tion Study in Rates.  Toxicol. Appl. Pharmacol., 30(2):
      287-298, 1974.

169.   Simmon, V. F., et al.  In Vitro Mutagenic Studies of Twenty
      Pesticides.  Toxicol. Appl. Pharmacol., 37(1):109, 1976.

170.   National Cancer  Institute Draft Summaries of Bioassay
      Reports.  Chem.  Reg. Rep.,  1 (45) :1608-1609, 1978.

171.   Grant, W. F.  Cytological Effects of Environmental Mutagens-
      Pesticides.  Mutat. Res., 21 (4) :221-222, 1973.

172.   Van Dijck, P., and H. Van de Voorde.  Mutagenicity Versus
      Carcinogenicity  of Organochloride Insecticides.  Meded.
      Fac. Landbouwwet., Rijksuniv. Gent, 41(2, part  2):1491-
      1498, 1976.

173.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 5,  1974.  pp.  157-171.

174.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 11, 1976.  pp. 131-139.

175.   Kurinnyi, A. I.  Mutagenic  Activity of  Some Pesticides
      Derivatives of Urea, Carbamic,  and Thiocarbamic Acids.
      Tsitol.  Genet.,  11 (4) :357-359.  1977.

176.   Hakeek,  H., and  A. Shehab.   Cytological Effects of Eptam
      and Cotoran on  Vioia Faba.   Egypt. J. Bot., 16 (1-3):303-
      311,  1974.

177.   Rydberg, U., and S. Skerfuing.  The Toxicity of Ethanol:
      A Tentative Risk Evaluation.  Adv. Exp. Med. Biol., 85B:
      403-419, 1977  (57 references).

178.   Braun, R., and J. Schoeneick.   Influences of Ethanol and
      Carbon Tetrachloride on the Mutagenic Effectivity of Cyclo-
      phosphamide in  the Host-Mediated  Assay  with Salmonella
      Typhimur-Lum-  Mutat. Res.,  31 (3) : 191-194,  1975.

179.   Charbey, R. C.,  et al.  Evaluation of the Effect of Ethanol
      on the Frequency of Micronuclei in the  Bone Marrow of  Swiss
      Mice.  Mutat. Res., 43 (3) :441-444, 1977.
                                 59

-------
180.   Opdyke,  D.  L.   Monographs on Fragrance Raw Materials Ethyl-
      benzene.   Food Cosmet.  Toxicol.,  13(Suppl.):803-804, 1975.

181.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man,  Volume 15, 1977.   pp.  195-209.

182.   Johns,  R.  Air Pollution Assessment of Ethylene Dibromide.
      National Technical Information Service No.  PB 256 736, 1976.

183.   New Findings on Two Carcinogens Reported to Subcommittee by
      NIOSH.   Occupational Safety & Health Reporter, 7(35):1331,
      1978.

184.   Johns,  R.  Air Pollution Assessment of Ethylene Bichloride.
      National Technical Information Service No.  PB 256 733, 1976.

185.   Homburger,  F.   Carcinogenicity of Several Compounds.
      National Technical Information Service No.  PB 183 027,
      1968.  26 pp.

186.   Mason,  M. M.  Toxicology and Carcinogenesis of Various
      Chemicals Used in the Preparation of Vaccines.  National
      Technical Information Service No. PB 195 185, 1969.  55 pp.

187.   Derse,  P. H.  Injection of Newborn Mice with Seven Chemical
      Adjuvants to Help Determine Their Safety.  National Tech-
      nical Information Service No. PB 195 153, 1969.  135 pp.

188.   Coon, R., et al.   Animal Inhalation Studies on Ammonia,
      Ethylene Glycol,  Formaldehyde, Dimethylamine, and Ethanol.
      Toxicol.  Appl. Pharmacol., 16 (3) : 645-646, 1970.

189.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man,  Volume 11, 1976.   pp.  157-167.

190.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man,  Volume 9, 1976.  pp. 37-46.

191.   Arcos,  J. C.,  and M. F. Argus.  Chemical Induction of Cancer,
      Volume  11A.  Academic Press, New York, 1974.  pp. 26, 237.

192.   Hoffman,  D., et al.  J. Natl. Cancer Inst., 49:1165-1175,
      1972.

193.   Rao, T.  K., et al.  Environmental Mutagenesis of Energy-
      Related Effluents.  Genetics, 83:S60, 1976.

194.   Watanabe, F.,  et al.  Gann, 45:451-452,  1954  (as cited in
      Reference 5).

195.   Investigation of Selected Potential Environmental Contami-
      nants:   Formaldehyde.  National Technical Information
      Service No. PB 256 839, 1976.

                                60

-------
196.   Alam,  M. T.,  and S. S. Kasatiya.  Cytological Effects of an
      Organic Phosphate Pesticide on Human Cells in Vitro.  Can.
      J. Genet. Cytol., 18 (4) :665-671, 1976.

197.   Jorgenson, T. A., et al.  In Vivo Mutagenesis Investiga-
      tions of Ten Commercial Pesticides.  Toxicol. Appl.
      Pharmacol., 37(1):109, 1976.

198.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 5, 1974.  pp. 173-191.

199.   Bioassay of Heptachlor for Possible Carcinogenicity, CAS
      No. 76-55-8.  National Technical Information Service No.
      PB 271  967.

200.   Khera,  K. S.  Hexachlorobenzene:  Teratogenicity and Domi-
      nant Lethal Studies  in Rats.  Toxicol. Appl. Pharmacol.,
      29 (1) :109, 1974.

201.   Boyland, E., et  al.  Kidney Tumors in Rats Following Treat-
      ment with 2-Acetylaminofluorene, Tryptophan, and 14-Sacchar-
      olactone and the Failure of Substances Which Cause
      Porphyrinuria to Induce Tumors.  In:  British Empire Cancer
      Campaign 1963 -  Part  2:  Scientific Report, 1963.  pp.  58-59,

202.   Guerzoni, M. E., et  al.  Mutagenic Activity of Pesticides.
      Riv. Sci. Tecnol. Alimenti Nutr. Urn.  (Ital.), 6(3):161-165,
      1976.

203.   Cabral, J. R. P.,  et  al.  Carcinogenic Activity of Hexachlo-
      robenzene in Hamsters.  Nature, 269(5628):510-511,  1977.

204.   Test for Carcinogenicity of Organic Contaminants of United
      States  Drinking  Waters by Pulmonary Tumor  Response  in a
      Strain  of Mice.  Cancer Res., 37 ( 8) :2717-2720, 1977.

205.   Results of a Two-year Chronic Toxicity Study with Hexachlo-
      robutadiene in Rats  (Meeting Abstract).  Toxicol. Appl.
      Pharmacol., 41(1):204, 1977.

206.   Kociba, R. J., et  al.  Results  of a Two-Year Chronic Toxi-
      city Study with  Hexachlorobutadiene in Rats.  Am. Ind.  Hyd.
      Assoc.  J., 38(11):589-602, 1977.

207.   Reproduction Study in Japanese  Quail Fed Hexachlorobuta-
      diene for 90 days.   Toxicol. Appl. Pharmacol., 30 (2):255-
      265, 1974.

208.   Delia Porta, G., et  al.  Non-Carcinogenicity  of Hexamethyl-
      enetetramine in  Mice  and Rats.  Food Cosmet.  Toxicol.,
      6(6):707-715, 1968.
                                 61

-------
209.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man,  Volume 5,  1974.   pp.  127-136.

210.   Roe, F.  J.  C.,  and M.  H. Salaman.   Further Studies on In-
      complete Carcinogenesis.  British  J.  of Cancer,  9:177-203,
      1955.

211.   Boyland, E., et al.   Further Experiments on Implantation of
      Materials into  the Urinary Bladder of Mice.  British J. of
      Cancer,  18:575-581,  1964.

212.   Van Duuren, B.  L., and B.  M. Goldschmidt.   Cocarcinogenic
      and Tumor-Promoting Agents in Tobacco.   J. Natl. Cancer
      Inst., 56:1237-1242, 1976.

213.   Hecht, S. S., et al.  Study of Tobacco Carcinogenesis; XIII:
      Tumor-Promoting Subfractions of the Weakly Acidic Fraction.
      J. Natl. Cancer Inst., 55 (6) :1329-1336, 1975.

214.   Interaction Between Hydroquinone and Cigarette Smoke Con-
      densate in Short-Term Skin Tests for Carcinogenicity.
      TOXLINE.

215.   National Cancer Institute Draft Summaries of Bioassay
      Reports.  Chem. Reg. Rep., 1(45):1602-1603, 1978.

216.   Silinskas, K. C.,  and A. B.  Okey.   Protection by DDT
      Against Mammary Tumors and Leukemia During Prolonged Feed-
      ing of 7,12-Dimethylbenz(a)anthracene to Female Rats.   J.
      Natl. Cancer Inst., 55 (3)  : 653-658, 1975.

217.   Dickens, F., and H. E. H. Jones.  Further Studies on the
      Carcinogenic and Growth-Inhibitory Activity of Lactones and
      Related Substances.  Brit. J. Cancer, 17:100-108, 1963.

218.   Evaluation of Carcinogenic,  Teratogenic, and Mutagenic
      Activities of Selected Pesticides  and Industrial Chemicals,
      Volume III.  National Technical Information Service No.
      PB  223 161, 1968.

219.   Evaluation of Carcinogenic,  Teratogenic, and Mutagenic
      Activities of Selected Pesticides  and Industrial Chemicals,
      Volume II.  National Technical Information Service No.
      PB  223 160, 1968.

220.   Ehrenberg, L.,  et al.  On the Reaction Kinetics and Muta-
      genic Activity of Methylating and Beta-Halogenoethylating
      Gasoline Additives.  Radiat. Bot., 14 (3) : 185-194, 1974.

221.   Embryo Toxicity and Feto Toxicity of Inhaled Carbon Tetra-
      chloride, 1,1-Dichloroethane, and Methyl Ethyl Ketone in
      Rats.  Toxicol. Appl. Pharmacol.,  29(1):123, 1974.

                               62

-------
222.   Nakahara, W.,  and K. Mori.  Proc. Imp. Acad., Japan,
      15:278-281, 1939 (as cited in Reference 5).

223.   Nakahara, W.,  and K. Mori.  Gann, 34:143-145, 1940  (as
      cited in Reference 5).

224.   Horton, A. W.,  et al.  Cancer Research, 25:1759-1763, 1965
      (as cited in Reference 5).

225.   Singh, A. R.,  et al.  Embryonic-Fetal Toxicity and Tera-
      togenic Effects of a Group of Methacrylate Esters in Rats.
      J. Dental Research,  51:1632-1638, 1972.

226.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume  4, 1974.  pp. 65-71.

227.   OSHA Compliance Guide,  29 CFR Part 1910, 1978.

228.   Methylene Chloride Passes Early Tests.  Chem. Eng. News,
      55(19):6, 1977.

229.   Mutation Research, Volume 53, January 1978.

230.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume  4, 1974.  pp. 79-85.

231.   Schoental,  R.  Carcinogenic and Chronic Effects of  4,4'-
      Diaminodiphenylmethane, an Epoxyresin Hardener.  Nature,
      219:1162-1163, 1968.

232.   Steinhoff,  D., and E. Grundmann.  Zur Cancerogenen Wirkung
      von 4,4'-Diaminodiphenylmethan und 2,4'-Diaminodiphenyl-
      methan.  Naturioissenschaften, 57:247-248, 1970.

233.   Gigiena  i Sanitariya, 34:40, 1969.  (Translated in Hygiene
      and Sanitation.)

234.   Toxic  Substances:  Proposed Occupational Safety and Health
      Standards for Alkyl  Benzenes, Cyclohexane, Ketones, and
      Ozone.   Fed. Regist. 40(196):47262-47313,  1975.

235.   Effect of Alpha-Methylstyrene and Tert-Dodecyl Mercaptan on
      the Skin of Animals.  Vop. Gig. Tr. Profzabol., Mater.
      Nauch. Konf.; 1972.  pp.  247-249.

236.   Reversible  Damage to the  Skin of Experimental Animals Sub-
      jected to the Inhalation  of Butadiene and  Alpha-Methyl-
      styrene.  Mater. Nauch. Sess., Posoyashck.  50-Letiyu
      Obrazov. SSSR, Omsk. Gas. Med. Inst.; 1972.  pp.  871-873.

237.   Effect of Isopropylbenzene and Alpha-Methylstyrene  on Leu-
      copoiesis.  Farmakol. Toksikol., 35 (4) :491-492, 1972.


                               63

-------
238.   Effect of the Wastes from Phenol Production on Housefly
      Larvas.   Mater.  Konf.  Molodykh.  Uch. Stud., Posvyashch.
      50-Letiyu SSSR;  1973.   pp. 375-377.

239.   Greenblatt, M.,  et al.  J. Natl. Cancer Inst., 46(5):1029-
      1034,  1971 (as cited in Reference 5).

240.   Sander,  J., and G. Bunkle.  Z.  Krebsforsch, 73(l):54-66,
      1969.

241.   Fomenko, V. N.,  and E. E. Strekalova.  Mutagenic Action of
      Some Industrial Poisons as a Function of Concentration and
      Exposure Time.  Toksikol. Nov.  Prom. Khim. Veshehestv.,
      13:51-57, 1973 (CA 79:143228).

242.   Migukina, N.  V.   Evaluation of  the Danger of Morpholine
      During Chronic Action.  Toksikol. Nov. Prom. Khim. Veshe-
      hestv-,  13:92-100, 1973  (CA 79:143345).

243.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 4, 1974.  pp. 87-96.

244.   OSHA Compliance Guide, 29 CFR Part 1910, 1004, 1978.
      pp. 298-300.

245.   Arcos, J. C., and M. F. Argus.   Chemical Induction of Can-
      cer, Volume IIA.   Academic Press, New York, 1974.  pp. 194,
      237, and 278.

246.   Kraemer, M.,  et al.  S. Typhimurium and E. Coli to Detect
      Chemical Mutagens.  Naunyn-Schmiedebergs Arch. Pharmakol.,
      284:46R, 1974.

247.   Zabezhinskiy, M.  A.  Investigations on Possible Carcino-
      genic Effects of Beta-Sevin.  Vopr. Onkol., 16(11):106-107,
      1970.

248.   Dorigan, J.,  and J. Hushon.  Air Pollution Assessment of
      Nitrobenzene.  National Technical Information  Service No.
      PB 257 776, May 1976.

249.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 1, 1972.  pp. 95-106.

250.   Bretschneider, K., and J. Matz.  Occurrence and Analysis of
      Nitrosamines in Air.  IARC Sci. Pub. No. 14, 1976.  pp. 395'
      399.

251.   Fine,  D. H.,  et al.  N-Nitroso Compounds in Air and Water.
      IARC Sci. Pub. No. 14, 1976.  pp. 401-408.
                              64

-------
252.   Tradiff,  R.  G., et al.  Halogenated Organics in Tap Water:
      A Toxicological Evaluation.  In:  The Environmental Impact
      of Water Chlorination, National Technical Information
      Service No.  CONF 751096, 1976.  pp. 213-228.

253.   Vogel, E., and J. L. R. Chandler.  Mutagenicity Testing of
      Cyclamate and Some Pesticides in Drosophila Melanogaster-
      Experientia, 30 ( 6) :621-623, 1974.

254.   Buselmaier,  W., et al.  Comparative Investigations on the
      Mutagenicity of Pesticides in Mammalian Test Systems.
      Mutat. Res.", 21(l):25-26,  1973.

255.   Daugherty, R. C., and K. Piotrowska.  Screening by Negative
      Chemical lonization Mass Spectrometry for Environmental
      Contamination with Toxic Residues:  Application to Human
      Urines.  Proc. Natl. Acad. Sci., 73 (6) :1777-1781, 1976.

256.   Salaman, M.  H., and 0. M.  Glendenning.  Brit. J. Cancer,
      11:434-444,  1957.

257.   Hossak, D. J., and J. C. Richardson.  Examination of the
      Potential Mutagenicity of  Hair Dye Constituents Using the
      Micronucleus Test.  Experientia, 33 (3) :377-378, 1977.

258.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 7, 1974.  pp. 261-289.

259.   Lloyd, J. W., et al.  Polychlorinated Biphenyls.  J. Occup.
      Med.,  18(2):109-113,  1976.

260.   Andrews, E.  J., et al.  PCB Diet.  Science, 180 (4083) :255-
      257, 1973.

261.   Ito, N., et al.  Histopathological Studies on Liver Tumori-
      genesis in Rats Treated with Polychlorinated Biphenyls.
      Gann,  65 ( 6)  :545-549,  1974.

262.   Lawrence, C.  PCB? and Melanoma  (letter to the  editor).
      N. Engl. J.  Med., 296 (2) :108-109,  1977.

263.   Gibel, W., et al.  Experimental Study on Cancerogenic
      Activity of Propanol-1, 2-Methylpropanol-l, and 3-Methyl-
      butanol.  Arch. Geschwulstforsch,  45(l):19-24,  1975.

264.   Gibel, W., et al.  Studies on the  Toxicity and  Mutagenicity
      of Single Fusel Oil Components on  E.  Coli.  Acta Biol. Med.
      Ger.,  23:843-852, 1969.

265.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 15, 1977.  pp. 223-243.
                                65

-------
266.   IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man,  Volume 11, 1976.  pp. 191-199.

267.   Rowe, L.  K., et al.   Toxicity of Propylene Oxide Determined
      on Experimental Animals.  Arch. Industr. Hlth., 13:228-236,
      1956.

268.   Arcos, J. C., and M.  F.  Argus.   Chemical Induction of Cancer,
      Volume IIA,  Academic  Press,  New York, 1974.  pp. 210, 237.

269.   Dickens,  F., et al.   Brit. J. Cancer, 20:134-144, 1966.

270.   Dickens,  F., and H.  B.  Wayforth.  Brit. Emp. Cane. Camp.,
      46:108, 1968.

271.   Dickens,  F., et al.   Brit. J. Cancer, 22:762-768, 1968.

272.   Grant, I. F., et al.   Long-Term Toxicity of Sorbic Acid in
      the Rat.   Food Cosmet.  Toxicol., 13(1):31-45, 1975.

273.   Hendy, R. J., et al.   Long-Term Toxicity Studies of Sorbic
      Acid in Mice.  Food Cosmet.  Toxicol., 14(5):381-386, 1976.

274.   Mason, P. L., et al.   Long-Term Toxicity of Parasorbic Acid
      in Rats.   Food Cosmet.  Toxicol., 14(5) :387-394, 1976.

275.   Kada, T.   Mutagenicity and Carcinogenicity Screening of
      Food Additives by the Rec-Assay and Reversion Procedures.
      IARC Sci. Pub. No. 12,  1976.  pp. 105-115.

276.   DeMeester, C., et al.  Mutagenic Activity of Styrene and
      Styrene Oxide.  Arch. Int. Physiol. Biochim., 85(2):398-
      399, 1977.

277.   Vainio, H.,  et al.  A Study on the Mutagenic Activity of
      Styrene and Styrene Oxide.  Scand. J. Work Environ. Health,
      2(3):147-151, 1976.

278.   Stolz, D. R.  Mutagenicity Testing of Styrene and Styrene
      Epoxide in Salmonella Typhimurium.  Bull. Environ. Contam.
      Toxicol., 17(6) :739-742", 1977.

279.   Loprieno, N., et al.   Mutagenicity of Industrial Compounds:
      Styrene and Its Possible Metabolite Styrene Oxide.  Mutat.
      Res., 40(4):317-324,  1976.

280.   Yeung, C. K. K., and C.  R. Phillips.   Estimation of Physio-
      logical Smog Sympton Potential from Chemical Reactivity of
      Hydrocarbons.  A tin.  Environ., 7,  1973.

281.   Gray, A.  W.  A.  Arch. Ind. Hyg.,  2:407-419, 1950.


                                66

-------
282.   Brem,  H., et al.  The Mutagenicity and DNA-Modifying Effect
      of Haloalkanes.   Cancer Res., 34:2576-2579, 1974.

283.   Rosenkranz, H. S.  Mutagenicity and DNA-Modifying Activity:
      A Comparison of Two Microbial Assays. ' Mutat. Res., 41(1):
      61-70, 1976.

284.   Kraybill, H. F.   Origin, Classification, and Distribution
      of Chemicals in Drinking Water with an Assessment of their
      Carcinogenic Potential.  In:  The Environmental Impact of
      Water Chlorination, National Technical Information Service
      No. CONF 751096, 1976.  p. 229.

285.   Chemical Regulation Reporter, 1(51):1861, 1978.

286.   Fuller, B. B.  Air Pollution Assessment of Tetrachloro-
      ethylene.  National Technical Information Service No.
      PB 256 731, 1976.  99 pp.

287.   Bioassay of Tetrachloroethylene for Possible Carcinogenicity,
      CAS No. 127-18-4.  National Technical Information Service
      No. PB 272 940, 1977.

288.   Epstein, S. S., and N. Mantel.  Carcinogenicity of Tetra-
      ethyl Lead.  Experientia, 24 (6) :580-581, 1968.

289.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 2, 1973.  pp. 150-160.

290.   Kennedy, G. L., et al.  Teratogenic Evaluation of Lead Com-
      pounds in Mice and Rats.  Food Cosmet. Toxicol., 3(6):629-
      632,  1975.

291.   Robinson, T. R.  Health, How Can It Be Measured.  In:  HEW
      Publ.  (NIOSH) 76-134, 1976.  pp. 114-130.

292.   Walker, P.  Air Pollution Assessment of Toluene.  National
      Technical Information Service No. PB 256 735, 1976.

293.   Giles, A. L., et al.  Dermal Carcinogenicity Study by
      Mouse-Skin Painting with 2,4-Toluenediamine Alone or in
      Representative Hair Dye Formulations.  J. Toxicol. Environ.
      Health, 1(3):433-440, 1976.

294.   Bridges, B. A., and M. H. Green.  Carcinogenicity of Hair
      Dyes  by Skin Painting in Mice  (letter to editor).  J.
      Toxicol. Environ. Health, 2(1):251-252, 1976.

295.   Shah, M. J., et al.  Comparative Studies of Bacterial Muta-
      tion  and Hamster Cell Transformation Induced by  2,4-Toluene-
      diamine  (Meeting Abstract).  Proc. Am. Assoc. Cancer Res.,
      18:22, 1977.

                                67

-------
296.   Cancer Research,  29:1137,  1969.

297.   Pienta,  R.  J.,  et al.   Correlation of Bacterial Mutagenicity
      and Hamster Cell  Transformations with Tumorigenicity Induced
      by 2,4-Toluenediamine.   Cancer Lett.  (Amsterdam), 3(1/2):
      45-52, 1977.

298.   Bioassay of 1,1,1-Trichloroethane for Possible Carcinogen-
      icity-  Carcinog. Tech.  Rep.  Serv. -  Nat'l. Cancer Inst.
      (U.S.);  ISS NCI-CG-TR-3,  1975.  70 pp.

299.   Carcinogenesis  Bioassay of Trichloroethylene,  CAS No. 79-
      01-6.   National Cancer  Institute Carcinogenesis Technical
      Report Services,  Number 2, February 1976 (NCI-CG-TR-2).

300.   Fuller,  B.  B.  Air Pollution  Assessment of Trichloroethyl-
      ene.  National  Technical Information  Service No. PB 256
      730, 1976.

301.   Epstein, S. S., et al.   Synergistic Toxicity and Carcino-
      genicity of "Freons" and Piperonyl Butoxide.  Nature, 214:
      526-528, 1967.

302.   Uehleke, H.,  et al.  Metabolic Activation of Haloalkanas
      and Tests in Vitro for  Mutagenicity.   Xenobiotica, 7(7):
      393-400, 1977.

303.   NCI Preliminary data on trichlorofluoromethane, Nov. 27,
      1976.

304.   Cytological Effects of  Pesticides.  V-   Effects of Some
      Herbicides  on Vicia Faba.   Cytologia, 39(4):663-643, 1974.

305.   IARC Monographs:   Evaluation  of the Carcinogenic Risk of
      Chemicals to Man, Volume 7, 1974.  pp.  111-140.

306.   Garibyan, D.  K.,  and S.  A. Papoyan.  Study of the Blasto-
      mogenic Activity of Certain Chemical  Substances Using a
      High-Speed Test Method.   Gig. Sanit., 8:74-76, 1977.

307.   Garibyan, D.  K.,  and S.  A. Papoyan.  Use of Sebaceous Gland
      Reactions as a Test for Rapid Determination of Carcinogenic
      Activity of Chemicals.   Nekot. Itogi  Izuch. Zagryazneniya
      Vnesh. Sredy Kanstserogen. Veschestoami; 112-115, 1972.

308.   Barbin,  A., et al.  Liver-Microsome-Mediated Formation of
      Alkylating Agents from Vinyl  Bromide and Vinyl Chloride.
      Biochem. Biophys. Res.  Comm., 67 (2) :596-603, 1975.

309.   IARC Monographs:   Evaluation  of the Carcinogenic Risk of
      Chemicals to Man, Volume 7, 1974.  pp.  291-305.
                                68

-------
310.   IARC Information Bulletin on the Survey of Chemicals Being
      Tested for Carcinogenicity.   International Agency for
      Research on Cancer, Lyon, Bulletin No. 5, July 1975.

311.   Greim, H. G., et al.  Mutagenicity in Vitro and Potential
      Carcinogenicity of Chlorinated Ethylenes as a Function of
      Metabolic Oxirane Formation.  Biochem. Pharmacol., 24:2013-
      2017, 1975.

312.   Food Additives, Packaging Material for Use During Irradia-
      tion of Pre-Packaged Foods.   Fed. Register, 33:4569, 1968.

313.   Caputo, A., et al.  Oncogenicity of Vinyl Chloride at Low
      Concentrations in Rats and Rabbits.  IRCS, 2:1582, 1974.

314.   Hushon, J., and M. Kornreich.  Air Pollution Assessment of
      Vinylidene Chloride.  National Technical Information
      Service No. PB 256 738, 1976.

315.   Pound, A. W.  Induced Cell Proliferation and the Initiation
      of Skin Tumor Formation in Mice by Ultraviolet Light.
      Pathology, 2(4):269-275, 1970.

316.   Listgarten, M. A., et al.  Ultrastructural Alterations in
      Hamster Cheek Pouch Epithelium in Response to a Carcinogen.
      Arch. Oral Biol., 8(2):145-165, 1963.

317.   Hecker, E.  Definitions and Terminology in Carcinogenesis -
      Analyses and Proposals  (Meeting Abstract).  Third Inter-
      national Symposium on Detection and Prevention of Cancer,
      1976.  p. 67.

318.   Yuspa, S. H., et al.  Cutaneous Chemical Carcinogenesis:
      Past, Present, and Future.  J. Invest. Dermatol., 67(1):
      199-208, 1976.

319.   Rogers, A. E.  Reduction of n-Nitrosodiethylamine Carcino-
      genesis in Rats by Lipotrope or Amino Acid Supplementation
      of a Marginally Deficient Diet.  Cancer Res., 37(1):194-
      199, 1977.

320.   Syrotuck, J. A., and B. S. Worthington.  Nutritional Effects
      on Syngeneic Tumor Immunity and Carcinogenesis in Mice, I.
      Selected Essential Amino Acids  (Meeting Abstract).  Fed.
      Proc., 36(3):1163, 1977.

321.   Leuchtenberger, C., and R. Leuchtenberger.  Protection of
      Hamster Lung Cultures by L-Cysteine Against Carcinogenic
      Effects of Fresh Smoke from Tobacco or Marihauana Cigar-
      ettes  (Meeting Abstract).  J. Cell. Biol., 70(2/Part 2):
      44a, 1976.
                                 69

-------
322.   Takamiua,  K.,  et al.   Effect of Phenobarbital and
      DL-Ethionine on 4-(Dimethylamino)azobenzene-Metabolizing
      Enzymes and Carcinogenesis.  Gann,  64(4):363-372, 1973.

323.   Ito,  N.,  et al.   The  Development of Carcinoma in Liver of
      Rats  Treated with m-Toluylenediamine and the Synergistic
      and Antagonistic Effects with Other Chemicals.  Cancer Res.,
      29 (5) :1137-1145, 1969.

324.   Radomski,  J. L., et al.   Cocarcinogenic Interaction Between
      D,L-Tryptophan and 4-Aminobiphenyl  or 2-Naphthylamine in
      Dogs.   J.  Natl.  Cancer Inst., 58 (6) :1831-1834, 1977.

325.   Ito,  N.,  et al.   Effect of Various  Carcinogenic and Non-
      carcinogenic Substances on Development of  Bladder Tumors
      in Rats Induced by n-Butyl-N-(4-hydroxybutyl)nitrosoamine.
      Gann,  65 (2) :123-130,  1974.

326.   Matsushima, M.  The Role of the Promoter L-Tryptophan on
      Tumorigenesis in the  Urinary Bladder.  2.   Urinary Bladder
      Carcinogenicity of Fanft  (Initiating Factor) and L-Tryptophan
       (Promoting Factor) in Mice.  Jpn.  J. Urol., 68 (8) :731-736,
      1977.

327.   Rogers, A. E., and P. M. Newberne.   Dietary Effects on
      Chemical Carcinogenesis in Animal  Models for Colon and
      Liver Tumors.   Cancer Res., 35(ll/Part 2) :3427-3431, 1975.

328.   Bjelke, E.  Dietary Vitamin A and  Human Lung Cancer.
      Int.  J. Cancer,  15(4):561-565, 1975.

329.   Prutkin,  L.  Inhibition of Tumorigenesis by Topical
      Application of Low Doses of Vitamin A Acid and Fluorouracil.
      Experientia, 31(4) :494,  1975.

330.   Sugimura,  T.  Carcinogens in Foods  and Food Products.
      Proceedings of the Eleventh Canadian Cancer Research
      Conference, Natl. Cancer Inst. Canada, Toronto, Ontario,
      6-8 May 1976,  1976.

331.   Schoental, R.   The Role of Nicotinamide and of Certain
      Other Modifying Factors in Diethylnitrosamine Carcinogenesis:
      Fusaria Mycotoxins and "Spontaneous" Tumors in Animals and
      Man.   Cancer  (Suppl.), 40 (4) :1835-1840 , 1977.

332.   Wattenberg, L. W., et al.  Dietary Constituents Altering
      the Response to Chemical Carcinogens.  Fed. Proc.,
      35:1327-1331,  1976.
                                70

-------
333.   Wattenberg,  L.  W.  Inhibition of Chemical Carcinogenesis
      by Antioxidants and Some Additional Compounds.  In:
      Fundamentals in Cancer Prevention, Proceedings of the 6th
      International Symposium of The Princess Takamatsu Cancer
      Research Fund (Tokyo, 1975) , The Princess Takamatsu Cancer
      Research Fund,  Tokyo, Japan, 1976.  pp. 153-166.

334.   Chowaniec, J.,  et al.  Histology of Tumour Formation in the
      Bladder of Rats Receiving Dietary Saccharin and a Single
      Dose of n-Methyl n-Nitrosourea (Meeting Abstract).   B. J.
      Cancer, 29 (1) :93,  1974.

335.   Hicks, R. M., and J. Chowaniec.  The Importance of  Synergy
      Between Weak Carcinogens in the Induction of Bladder Cancer
      in Experimental Animals and Humans.  Cancer Res., 37(8,
      Part 2):2943-2949, 1977.

336.   Roe, F. J.,  et al.  Feeding Studies on Sodium Cyclamate,
      Saccharin and Sucrose for Carcinogenic and Tumour-Promoting
      Activity.  Food Cosmet. Toxicol., 8(2):135-145, 1970.

337.   Nomura, T.  Inhibitory Effect of Caffeine on Chemical
      Carcinogenesis in Mice  (Meeting Abstract).  Proc. Am. Assoc.
      Cancer Res., 18:244, 1977.

338.   Challis, B.  C., and C. D. Bartlett.  Possible Cocarcinogenic
      Effects of Coffee Constitutents.  Nature  (Lond.), 254(5500):
      532-533, 1975.

339.   Watanabe, K., et al.  Effect of Bile Acids and Neutral
      Sterols on Benzo(a)pyrene-Induced Tumorigenesis  in Skin of
      Mice:  Brief Communication.  J. Natl. Cancer Inst., 60(6):
      1501-1503, 1978.

340.   Altman, R. F.,  et al.  Phospholipids Retard and Cholesterol
      Promotes the Formation of Tumours Induced by Carcinogenic
      Hydrocarbons.  Z. Naturforsch. (B) , 23 (9):1277-1279,  1968.

341.   Bingham, E., et al.  Multiple Factors  in Carcinogenesis.
      Ann. N.Y. Acad. Sci. , 271:14-21,  1976.

342.   Blunck, J. M.,  and C. E. Crowther.  Enhancement  of Azo Dye
      Carcinogenesis by Dietary Sodium Sulphate.  Eur. J. Cancer,
      11(1):23-31, 1975.

343.   Homburger, F.,  and E. Boger.  The Carcinogenicity of
      Essential Oils, Flavors, and Spices:  A Review.  Cancer
      Res.,  28(11):2372-2374, 1968).

344.   Salaman, M.  H., and F. J. Roe.  Cocarcinogenesis.  Br. Med.
      Bull., 20(2):139-144, 1964.
                               71

-------
345.   Schramm,  R.,  and W.  Gibel.   Carcinogenic and Cocarcinogenic
      Plant Products,  II.   Carcinogenic Substances Synthesized by
      Pteridophyta  (Filicinae)  and Spermatophyta (Cyadineae,
      Dicotyledoneae,  Monocotyledoneae).   Arch.  Geschwulstforsch.,
      33(2):169-188,  1969.

346.   Zschiesche, W.,  and  G.  Bruns.   Carcinogenesis of
      7-Ketocholesterol.   Oncology,  18(4):289-299,  1964.

347.   Bryson,  G., and F. Bischoff.  Triolein as  a Cocarcinogen.
      Fed.  Proc.,  23(2,  Pt.  1):106,  1964.

348.   Dzagnidze,  L.  I.,  and P.  N.  Krasniyanskaya.  A Study of
      Possible Carcinogenic and Cocarcinogenic Properties of
      Overheated  Oils.  Soobshch.  Akad.  Nauk.  Gruz. SSR, 67(1):
      229-231,  1972.

349.   Dayton,  S., et al.   Effect of  High-Oleic and High-Linoleic
      Safflower Oils on Mammary Tumors  Induced in Rats by 7,12-
      Dimethylbenz(alpha)anthracene.  J.  Nutr.,  107(8):1353-1360,
      August 1977.

350.   Sinnhuber,  R.  0.,  et al.   Metabolism and Cocarcinogenicity
      of Cyclopropenes.  Oregon State Higher Educ.  Sys., School of
      Agriculture,  Food Science and  Technology,  Corvallis, Oregon.

351.   Lee,  D.  J., et al.   Synergism Between Cyclopropenoid Fatty
      Acids and Chemical Carcinogens  in Rainbow Trout (Salmo
      Gairdneri).   Cancer  Res., 28(11):2312-2318, 1968.

352.   Petering H. G.   Diet,  Nutrition,  and Cancer.   Adv. Exp.
      Med.  Biol.,  91:207-228,  1977.

353.   Raikow,  R.  B.   Effects of Carcinogens or Suspected
      Carcinogens on Viral Luekemogenesis in C57BL/10, SJL/J Mice
      and Their Fl  Hybrid  (Meeting Abstract).   Proc.  Am. Assoc.
      Cancer Res.,  19:23,  1978.

354.   Rice,  E.  W.   Furfural:   Exogenous Precursor of Certain
      Urinary Furans and Possible Toxicologic Agent in Humans.
      Clin.  Chem.,  18(12):1550-1551,  1972.

355.   Ruchkovskii,  B.  S.,  et al.   Carcinogenic and Cocarcinogenic
      Action of Dried Fruit Extract.  Vopr. Onkol., 20(4):58-61,
      1974.

356.   Rothman,  K. J.   The  Effect of  Alcohol Consumption on Risk
      of Cancer of  the Head and Neck.  (Head and Neck Cancer,
      State-of-the-Art Conference, St.  Louis,  Mo.,  February 16-18,
      1976.)   Laryngoscope,  88(1,  Part  2,  Suppl. 8):51-55, 1978.
                               72

-------
357.   Bross,  I.  D.,  and J.  Coombs.   Early Onset of Oral Cancer
      Among Women Who Smoke and Drink.   Proc.  Am.  Assoc. Cancer
      Res., 17:1,  1976.

358.   Gibel,  W.,  and G.  Wittig.  On the Experimental Induction of
      Carcinoma  of the Esophagus.  Dtsch. Gesundheitsw., 19(14):
      635-637,  1964.

359.   Radike, M.  J.,  et al.  Effect of  Ethanol and Vinyl Chloride
      on the  Induction of Liver Tumors:  Preliminary Report.
      Environ.  Health Perspect.,  21:153-155, 1977.

360.   Jayant, K.   Statistical Appraisal of the Association of
      Smoking and Chewing Habits to Oral and Pharyngeal Cancers.
      Indian  J.  Cancer,  14 (4) :293-299,  1977.

361.   Ranadive,  K. J., et al.  Experimental Studies on Betel  Nut
      and Tobacco Carcinogenicity.   Int. J. Cancer, 17(4) : 469-476 ,
      15 April  1976.

362.   Hecht,  S.  S.,  et al.  Chemical Studies on Tobacco Smoking
      Determination of Hydroxybenzyl Alcohols  and  Hydroxyphenyl
      Ethanols  in Tobacco and Tobacco Smoke.  J. Anal. Toxicol.,
      2(2):56-59, 1978.

363.   DiPaolo,  J. A., and P. J. Donovan.  In Vitro Morphologic
      Transformation of Syrian Hamster  Cells by U.V.-Irradiation
      is Enhanced by X-Irradiation and  Unaffected  by Chemical
      Carcinogens.  Int. J. Radiat. Biol., 30(l):41-53, July  1976.

364.   Palotay,  J. L., et al.  Carcinogen-Induced Cutaneous
      Neoplasms in Nonhuman Primates.  J. Natl. Cancer Inst.,
      57(6):1269-1274, 1976.

365.   Lohsoonthorn,  P.  The Epidemiologic Study of Subsite Large
      Bowel Cancer.   Diss. Abstr. Int.   (B) , 36 (9) :4399-B,  1976.

366.   Werner, B., et al.  Cholecystectomy and Carcinoma of the
      Colon,  An Experimental Study.  Z. Krebsforsch., 88(3) :223-
      230,  1977."

367.   Williamson, R.  C., et al.  The Effect of Pancreatobiliary
      Diversion on Testical Carcinogenesis  (Meeting Abstract).
      Br. J.  Surg.,  64(11) :837, 1977.

368.   Reddy,  B.  S.  Role of Bile Metabolites in Colon Carcino-
      genesis.   Cancer  (Suppl.), 36:2401-2406, 1975.

369.   Reddy,  B.  S.,  et al.  Promoting Effect of Bile Acids on
      Colon Carcinogenesis in Germfree and Conventional Rats
      (Meeting  Abstract).  Proc. Am. Assoc. Cancer Res., 18:119,
      1977.
                                73

-------
370.   Wynder,  E.  L.   Metabolic Epidemiology of Colon Cancer.
      Amer.  Health Foundation, Inc.,  New York, New York.

371.   Curtis,  G.  L.,  et al.   Enhancement of 7,12-Dimethyl-
      benzanthracene  Skin Carcinogenesis by Adenosine, 3',5'-
      Cyclic Monophosphate.   Cancer Res., 34 (9) :2192-2195, 1974.

372.   Freund,  H., et  al.   Breast Cancer Arising in Thoracotomy
      Scars  (Letter to Editor).   Lancet, 1(7950):97, 1976.

373.   Glaser,  A.   Pathologic and Clinical Aspects of Bone Tumors.
      Zentralbl.  Chir., 101(6):321-329, 1976.

374.   Lung Cancer and Chronic Bronchitis.  Med.  M. Aust.,  51(24):
      926-927, 1964.

375.   Stenback,  F.,  and G. Curtis.   Mechanism of Action of Poly-
      cyclic Hydrocarbon Carcinogens:  Immunological Aspects
      (Meeting Abstract).  Scand.  J.  Immune1., 6(11):1196, 1977.

376.   Fukushima,  S.,  et al.   Effects  of Foreign Bodies on Gastric
      Carcinogenesis  in Rats Treated  with n-Methyl-n'-nitro-n-
      nitrosoguanidine (MNNG).  (Proc. Jpn. Cancer Assoc., 33rd
      Annual Meeting, October 1974.)   Gann, 67,  1975.
                                        i

377.   Kogan, A.  K. H., and V.  I. Kulitskaia.  The Effect of a
      Stationary Magnetic Field on Induced Carcinogenesis.  Patol.
      Fiziol.  Eksp.  Ter., (2):63-68,  1977.

378.   Suzuki,  S.   Effect of  Rotary Motion on Carcinogenesis.
      J. Nagoya City  Univ. Med.  Assoc., 19(4):1517-1558, 1969.

379.   Harris,  C.  C.   The Carcinogenicity of Anticancer Drugs:  A
      Hazard in Man.   Cancer,  37 (2) :1014-1023 , 1976.

380.   Arseneau,  J. C., et al.   Synergistic Carcinogenic Effect of
      Procarbazine and Ionizing Radiation in CDF Mice.  Proc. Am.
      Assoc. Cancer Res., 16:120,  1975.

381.   Kosir, A.   Contribution of Carcinogenesis.   Acta Med.
      lugosl., 16(2) :172-180," 1962.

382.   Medina,  D.   Enhancement of Mammary Tumor Formation in Mice
      by a"Cytostatic Drug,  Melphalan.  Cancer Res., 37(1):317-
      319, 1977.

383.   Wang,  C. Y., and S. Hayashide.   Enhancement of N-[4-(5-nitro-
      2-furyl)-2-thiazolyl]formamide  (FANFT) Carcinogenicity for
      Rat Urinary Bladder by Allopurinol.  Proc.  Am. Assoc. Cancer
      Res.,  17:149,  1976.
                                74

-------
384.   Maize, J. C.  Skin Cancer in Immunosuppressed Patients.
      JAMA, 237 (17) :1857-1858, 1977.

385.   IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 10, 1976.  pp. 153-161.

386.   Vesselinovitch, S. D., and N. Mihailovich.  The Inhibitory
      Effect of Griseofulvin on the "Promotion" of Skin
      Carcinogenesis.  Cancer Res., 28 (12):2463-2465, 1968.

387.   Langbein, W.  Contribution to the Cocancerogenic Effect of
      Cignolin in Animals.  Radiobiol. Radiother. (Berl.),
      13 (2):233-240, 1972.

388.   Weisburger, J. H., et al.  Modification of Diethylnitros-
      amine Liver Carcinogenesis with Phenobarbital but Not with
      Immunosuppression.  J. Natl. Cancer inst., 54(5):1185-1188,
      1975.

389.   Kitagawa, T.,  and H. Sugano.  Enhancement of Azo-Dye
      Hepatocarcinogenesis with Dietary Phenobarbital in Rats.
      Gann, 68 (2):255-256, 1977.

390.   Van Duuren, B. L.  Tumor-Promoting and Cocarcinogenic Agents
      in Chemical Carcinogenesis.  In:  Chemical Carcinogens,
      Searle, C.  E., ed., American Chemical Society Monograph
      1973, American Chemical Society, Washington, B.C., 1976.
      pp. 24-51.

391.   Slaga, T. J.,  et al.  Mechanism of Action of Steroidal
      Anti-Inflammatory Agents that Inhibit Skin Carcinogenesis.
      Proc. Am. Assoc. Cancer Res., 16:37, 1975.

392.   Kawaguchi,  K.   Studies on Experimental Induction of
      Endometrial Carcinoma in Rabbits, Especially Related to
      Their Carcinogenesis  (Meeting Abstract).  Acta Obstet.
      Gynaecol. Jpn., 21(1):68, 1976.

393.   Muhlbock, 0.,  and L. M. Boot.  The Mode of Action of Ovarian
      Hormones in the Induction of Mammary Cancer in Mice.  Bio-
      chem. Pharmacol., 16 (4):627-630, 1967.

394.   Warren, S., and 0. Gates.  Radiation Carcinogenesis,
      Progress Report IV, 15 March 1976 - 15 May 1977.  Available
      through National Technical Information Service, Springfield,
      VA, as COO-3017-31, EY-76-S-02-3017, 1977.  15 pp.

395.   Lee, C., et al.  In Vitro Interaction of Estrogen and
      Prolactin on Hormone-Dependent Rat Mammary Tumors  (38511).
      Proc. Soc.  Exp. Biol. Med., 148 (1):224-226, 1975.
                                75

-------
396.   Forsberg,  J.  G.,  and L.  S.  Breistein.   A Synergistic Effect
      of Oestradiol and Prolactin Influencing the Incidence of
      3-Methylcholanthrene Induced Cervical  Carcinomas in Mice.
      Acta Pathol.  Microbiol.  Scand (A),  84(5):384-390,  1976.

397.   Vorherr,  H.   Contraception  Postabortion and Postpartum,
      Advantages and Disadvantages of Hormonal Contraceptive with
      Particular Reference to  the Relationship Between Female Sex
      Hormones  and Thromboembolism and Carcinoma of the Breast
      and Genitals.  Gynaekol.  Rundsch.,  15(l):48-73, 1975.

398.   Lemon, H.  M.   Estriol and Prevention of Mammary Carcinoma.
      Cancer Detec. Prevent.,  1(2):263-281,  1976.

399.   Welsch. C. W.  Effects of a Norethynodrel-Mestranol
      Combination  (ENOVID) on  Development and Growth of
      Carcinogen-Induced Mammary  Tumors in Female Rats.   Cancer,
      23(3):601-607, 1969.

400.   Chevrel,  B.   Role of Steroid Hormones  in the Development
      of Malignant Tumors (Letter to Editor).  Nouv. Presse. Med.,
      5(17):1145,  1976.

401.   Gurkalo,  B.  K., and M. A. Zabezhinsky.   Modification of
      Chemical  Carcinogenesis  with Adrenergic Compounds.   Vestn.
      Akad. Med. Nauk SSSR, (2):38-42, 1978.

402.   Schmeltz,  I., et al.  Formation and Determination of
      Naphthalenes in Cigarette Smoke.  Anal. Chem., 48(4):645-
      650,  1976.

403.   Argus, M.  F., and J. C.  Arcos.  Hydrocarbon-Nitrosamine
      Synergism as a Possible  Amplying Factor in Lung Tumori-
      genesis by Tobacco Smoke.  J. Theor. Biol., 56 (2) :491-498,
      1976.

404.   Bock, F.  G.   Cocarcinogenic Activity of Nicotine.   Proc.  Am.
      Assoc. Cancer Res.,  17:2, 1976.

405.   Etiology  of Nasopharyngeal Carcinoma.   Lancet, 2 ( 8000) :1393,
      1976.

406.   DeMicco-Pagis, C., et al.  Pathologic  and Ultrastructural
      Investigation of a DMBA-Induced Transplantable Melanoma
      in the Golden Hamster.  Bull Cancer (Paris), 63(l):73-86,
      1976.

407.   Stepanova, L. G., et al.   DNA Reparation and Chromosome
      Aberrations in Human Cells Infected with LPV Oncornavirus.
      Vopr. Virusol.,  (6):712-716, 1977.
                               76

-------
408.   Bryan, W. R.  Current Concepts of Viral Neoplasia.  South.
      Med. J., 57(11):1263-1267, 1964.

409.   Mazzucco, K.  The Effect of Various Solvents  (Benzene,
      Toluene, Acetone) Used with Carcinogens on the Collagen
      Content of the Mouse Dorsal Skin.  Osterr. Z. Onkol.,
      2(2-3):49-51, 1975.

410.   Bingham, E., and H. L. Falk.  Environmental Carcinogens,
      The Modifying Effect of Cocarcinogens on the Threshold
      Response.  Arch. Environ. Health, 19(6):779-783, 1969-

411.   Bingham, E., and P. J. Nord.  Cocarcinogenic Effects of
      n-Alkanes and Ultraviolet Light on Mice.  J. Natl. Cancer
      Inst.,  58 (4) :1099-1101, 1977.

412.   Tanaka, T.   Influence of n-Dodecane on Rats Exposed Trans-
      placentially to Benzo(a)pyrene and Nitrosomethylurethan
      During  Pregnancy  (Meeting Abstract).  Third International
      Symposium on Detection and Prevention of Cancer, 1976.
      pp. 286-287.

413.   Horton, A. W.  Cellular Mechanisms of Chemical Carcino-
      genesis.  National Technical Information Service No. PB
      225 631, 1973.  91 pp.

414.   Mori, H., et al.  Effect of Carbon Tetrachloride on
      Carcinogenicity of Petasites Japonicus, and Transplant-
      ability of Induced Tumors.  Gann, 68 (6) :841-845, 1977.

415.   Mirme,  H.  Modifying Effect of Water-Soluble Shale Phenols
      on Carcinogenesis.  Vopr. Profil. Zagryaz. Okruzhayushchei.
      Chel. Sredy  Kantserogennymi Veshchestvami; 16-18, 1972.

416.   Hecker, E.   Aspects of Cocarcinogenesis.  In:  Scientific
      Foundations  of Oncology, T. Symington and R. L. Carter,
      eds., William Heinemann Medical Books, Ltd., Chicago,
      1976.   pp. 310-318.

417.   Falk, H. L.  Possible Mechanisms of Combination Effects in
      Chemical Carcinogenesis.  Oncology, 33 (2):77-85, 1976.

418.   Pershagen, G., et al.  Mortality in a Region Surrounding an
      Arsenic Emitting Plant.  Environ. Health Perspect., 19:133-
      137,  1977.

419.   Gargus, J. L., et al.  Utilization of Newborn Mice  in  the
      Bioassay of  Chemical Carcinogens.  Toxicol. Appl. Pharmacol.,
      15 (3):552-559, 1969.
                                77

-------
420.   Sakharov,  I.  I.,  et al.   The Cocarcinogenic Activity of
      Sulfonol NP-1.   Gig.  Tr.  Prof.  Zabol.,  (9):56-58, 1973.

421.   Pyleva,  Z.  A.,  et al.  Data on the Biological Properties of
      Olefin Sulfate.   Vopr.  Onkol.,  24(1):55-60, 1978.

422.   Loewengart, G.,  and B.  L.  Van Duuren.   Evaluation of
      Chemical Flame  Retardants for Carcinogenic Potential.
      J. Toxicol. Environ.  Health, 2(3):539-546, 1977.

423.   Arrhenius,  E.,  et al.  Disturbance of Microsomal Detoxica-
      tion Mechanisms  in Liver  by Chlorophenol Pesticides.  Chem.
      Biol. Interact.,  18(l):35-46, 1977.

424.   Arkhipov,  G.  N.,  and I. N.  Kozlova.   Study of the Carcino-
      genic Properties  of the Herbicide, Amine Salt of 2,4-
      Dicholorphenoxyacetic Acid.  Vopr. Pitan. , (5) -.83-84, 1974.

425.   Uchiyama,  M.,  et al.   Cocarcinogenic Effect of DDT and PCB
      Feeding on Methylcholanthrene-Induced Chemical Carcino-
      genesis.  Bull.  Environ.   Contam.  Toxicol., 12(6):687-693,
      1974.

426.   Nagasaki,  H.,  et al.   Analysis of  Various Factors on Liver
      Carcinogenesis  in Mice Induced by  Benzene Hexachloride (BHC)
      and Technical Polychlorinated Biphenyls  (PCBs).   J.  Nara.
      Med. Assoc.,  25 ( 6) :635-648, 1974  (Reed. 1975).

427.   Capuco,  A.  V.   Ammonia:   A Modulator of 3T3 Cell Growth.
      Diss. Abstr.  Inst.  (B),  38(9):4085,  1978.

428.   Rubin, D.,  and  I. S.  Levij.  Chemical Carcinogenesis in the
      Hamster Cheek Pouch:   Influence of Inhibitors and Inducers
      of Alkaline Phosphatase.   Pathol.  Microbiol.  (Basel),
      43 (1) :26-30,  1975.

429.   Lane, B. p.,  and M. J.  Mass.  Carcinogenicity and Cocarcino-
      genicity of Chromium Carbonyl in Heterotopic Tracheal Grafts
      Cancer Res.,  37(5):1476-1479, 1977.

430.   Hayatsu, H.,  et al.  Potential Cocarcinogenicity of Sodium
      Hypcchlcrite.   Nature (Lend.), 233 (5320)  :495, 1971.

431.   Nagata,  C., et  al.   Effect cf Hydrogen Peroxide, Fenton's
      Reagent, and Iron Ions on the Carcinogenicity of 3,4-
      Benzopyrene.   Gann, 64(3):277-285, 1973.

432.   Deichmann,  W.  B., and J.  L. Radomski.  Synergism Among Oral
      Carcinogens and  Tumorigens, Report of Preliminary Experi-
      ments.  Toxicol.  Appl.  Pharmacol., 6(3) :343-344, 1964.
                               78

-------
433.   Breedin,  P.  H.,  and D.  H.  Buss.   Ferruginous (Asbestos)
      Bodies in the Lungs of  Rural Dwellers, Urban Dwellers, and
      Patients  with Pulmonary Neoplasms.  South. Med.  J.,
      69(4):401-404, 1976.

434.   Einbrodt, H. J.   Combined Effort of Fine Dust on the Lung.
      Staub Reinhaltung Luft, 36 (3) :122-126, 1976.

435.   Rom,  W.  N.,  and A. M. Langer.   Carcinogenicity of Fibrous
      Glass (Letter to Editor).   West. J. Med., 126(5):413, 1977.

436.   Nordenson, I., et al.  Occupational and Environmental Risks
      in and Around a Smelter in Norther Sweden, II.   Chromosomal
      Aberrations in Workers  Exposed to Arsenic.  Hereditas,
      88(1) -.47-50, 1978.

437.   Ishinishi, N., et al.  Preliminary Experimental  Study on
      Carcinogenicity of Arsenic Trioxide in Rat Lung.  Environ.
      Health Perspect., 19:191-196,  1977.

438.   Uzawa, T.  Histopathological Studies on Pulmonary Reaction
      by Beryllium Oxide in Rat (Experimental Tumorous Action  of
      BEO Combined with Carcinogenic Hydrocarbons).  Bull. Tokyo
      Med.  Dent. Univ., 9(3):440,  1963.

439.   Nettesheim, P., et al.   Carcinogenic and Cocarcinogenic
      Effects of Inhaled Synthetic Smog and Ferric Oxide Par-
      ticles.  J. Natl. Cancer Inst.,  55 (1) :159-169,  1975.

440.   Sellakumar, A., et al.   Effects of Different Dusts on
      Respiratory Carcinogenesis in Hamsters Induced by Benzo-
      (a)pyrene and Diethylnitrosamine.  Eur. J. Cancer,  12(4):
      313-319,  1976.

441.   Bock, F.  G., et al.  Cocarcinogenic Activity of  Peroxy
      Compounds.  J. Natl. Cancer Inst., 55(6):1359-1361,  1975.

442.   Kripke, M. L., and T. Borsos.   Accelerated Development of
      Benzo(a)pyrene-Induced Skin Tumors in Mice Treated with
      Pyran Copolymer.  J. Natl. Cancer. Inst., 53 (5)  :1409-1410,
      1974.

443.   Shapiro,  R.  Genetic Effects of Bisulfite (Sulfur Dioxide).
      Mutat. Res., 39 ( 2) :149-176 ,  1977.

444.   Galop, J., et al.  A Study of the  Influence of Trace
      Elements on the Hydroxylation of Benzo(a)pyrene.  Eur. J.
      Toxicol.  Environ. Hyg., 9(5):271-286, 1976.
                               79

-------
445.   Shimkin,  M.  B.,  et al.   Lung Tumor Response in Mice to
      Metals and Metal Salts.   Adv.  Exp. Med.  Biol., 91:85-91,
      1977.

446.   Kobayashi, N.,  and T. Okamoto.  Effects  of Lead Oxide on
      the Induction of Lung Tumors in Syrian Hamsters.  J. Natl.
      Cancer Inst.,  52 ( 5) :1605-1610, 1974.

447.   Cardesa,  A., et al.   The Syncarcinogenic Effect of Methyl-
      cholanthrene and Dimethylnitrosamine  in  Swiss Mice
      Z.  Krebsforsch., 79 ( 2) : 98-107 , 1973.

448.   Danz,  M., et al.  Prevention of 2-Acetylaminofluorene-
      Induced Extrahepatic  Short-Term Effects  by 3-Methyl-
      cholanthrene.   Exp.  Pathol.  (Jena), 13(4-5):262-267, 1977.

449.   Cardesa,  A., et al.   Effects of Intraperitoneal Injections
      of Dimethyl- and Diethylnitrosamine,  Alone or Simultaneously
      on Swiss Mice.   Z. Krebsforsch.,  82(3):233-238 , 1974.

450.   Topping,  D.  C.,  et al.   The  Interaction  of Benzo(a)pyrene
      and Benzo(e)pyrene in Respiratory Tract  Carcinogenesis
      (Meeting Abstract).   Proc. Am. Assoc. Cancer  Res., 19:43,
      1978.

451.   Mondal, S.,  et al.  Syncarcinogensis  in  Cultured C3H/10T1/2
      Cells   (Meeting Abstract). Proc.  Am.  Assoc.  Cancer Res.,
      18:8,  1977.

452.   Palmer, M. S.,  et al.  Effect of Ozone on Benzpyrene
      Hydroxylase Activity  in the  Syrian Golden Hamster.  Cancer
      Res.,  31(6):730-733,  1971.

453.   Sellakumar,  A.  R., et al.  Influence  of  Croton Oil in
      Hamster Lung Carcinogenesis.  Proc. Am.  Assoc. Cancer Res.,
      16:57, 1975.
                                       i
454.   Becker, E.  Cocarcinogenic Agents Derived from
      Euphorbiaceae.   Planta.  Med.,  1968:24-25, 1968.

455.   Hecker, E.  New Toxic,  Irritant,  and  Cocarcinogenic
      Diterpene Esters from Euphorbiaceae and from Thymelaeaceae.
      Pure Appl. Chem.,  59  (9) :1423-1431, 1977.

456.   zor Hausen,  H.  Z., et al.  Persisting Oncogenic Herpesvirus
      Induced by the Tumour Promoter TPA.  Nature  (Lond.),
      272(5651) :373-375, 1978.

457.   Komitowski,  D.,  et al.   Epidermal Intercellular Relationships
      During Carcinogenesis and Cocarcinogenesis as Revealed by
      Scanning Electron  Microscopy.   Virchows  Arch. (Cell Pathol.),
      24 (4) :317-333,  1977.


                               80

-------
458.   Janoff, A., et al.  Local Vascular Changes Induced by the
      Cocarcinogen, Phorbol Myristate Acetate.  Cancer Res.,
      30 (10) :2567-2571, 1970.

459.   Soper,  C. J., and F. J. Evans.  Investigations into the
      Mode of Action of the Cocarcinogen 12-O-Tetradecanoyl-
      phorbol-13-acetate Using Auxotrophic Bacteria.  Cancer
      Res., 37(8, Part 1):2487-2491, 1977.

460-   Tsuda,  H., et al.  Synergistic Effect of Urinary Bladder
      Carcinogenesis in Rats Treated With n-Butyl-N-(4-hydroxy-
      butyl)nitrosamine, n-[4- (5-Nitro-2-furyl)-2-thiazolyl]-
      formamide, n-2-Fluorenylacetamide, and 3,3'-Dichloroben-
      zidine.  Gann, 68 (2) :183-192, 1977.

461.   Kallistratos, G.  Prevention  of 3,4-Benzpyrene Carcino-
      genesis by Naturally Occurring and Synthetic Compounds.
      Muench. Med. Wochenschr., 117 (10) :391-394, 1975.

462.   Truhaut, R., et  al.  Inhibitor Effect of Ellipticine
      [Dimethyl-5, II-(6H) Pyrido  (4,3-B Carbazole) on Rat Liver
      Carcinogenesis Induced by BT6  (n,n-Dimethyl-p-benzo-
      thiazolylazo) Aniline]:  Incidences on Cytochrome P450 and
      Arginase Activity  (Meeting Abstract).  Fourth Meeting of
      the European Association for  Cancer Research  (held at
      Universite de Lyon, September 13-15, 1977),  European
      Association  for  Cancer Research, Lyon, France, 1977.  p. 86,
                                81

-------
                           APPENDIX A

     A REVIEW OF THE CARCINOGEN LITERATURE OF 125 CHEMICALS
INTRODUCTION

The first task of EPA Contract 68-02-2773 is to identify 20 sig-
nificant atmospheric carcinogens.  Sampling and analytical method-
ology based on porous polymer sorbents and gas chromatography/mass
spectrometry will then be developed for 15 of these chemicals.

In order to identify significant carcinogens, the literature has
been reviewed for about 125 chemicals to determine whether they
should be considered carcinogens for this project.  The results
for each chemical are given in this appendix.  An index to the
chemicals precedes the results.

Different criteria must be used to define what test results indi-
cate carcinogenicity depending on the use for which the resulting
list is intended.  For this program, some chemicals have been
included on the possible carcinogen list based on a limited
amount of short-term mutagenicity data.  If these lists should
be used for other purposes, it would be expedient to review the
literature cited and draw the appropriate conclusions based on
other guidelines.

For this project, a probable carcinogen generally has at least
some positive animal data coupled with positive mutagenicity data
from at least one well-established mutagenicity test or several
mutagenicity tests which have not been as extensively validated.
The mutagenicity tests which were considered fairly well estab-
lished include the Ames Salmonella typhimurium test and the
enhancement of viral transformation tests  (e.g., B. C. Casto),
with the E. coli-  (pol A) differential toxicity and the Drosophila
tests also considered important.

Animal carcinogenicity tests were considered less significant if
they were conducted more than 5 to 10 years ago, tested by the
subcutaneous route of administration demonstrating only local
tumors, utilized only a few animals, or reported no concurrent
control animals.

Dr. B, C. Casto, BioLabs, Inc., Northbrook, Illinois, has been a
consultant for Monsanto Research Corporation on this EPA contract.
                                 82

-------
                              INDEX

Chemical                                                     Page

Acetaldehyde                                                   86
Acetone                                                        87
Acetonitrile                                                   88
Acrolein                                                       89
Acrylonitrile                                                  90
Aldrin                                                         91
Allyl Chloride                                                 92
Aniline                                                        93
Anthracene                                                     94
Benz(a)anthracene                                              95
Benzene                                                        95
Benzidine                                                      97
Benzo(a)pyrene                                                 98
Benzoquinone  (Quinone)                                         99
Benzoyl Peroxide                                              100
Benzyl Chloride                                               101
Biphenyl                                                      102
Bis(chloromethyl) Ether                                       103
Butadiene                                                     104
Captan                                                        105
Carbon Bisulfide                                              106
Carbon Tetrachloride                                          107
Chloracetic Acid                                              108
Chlordane                                                     109
Cresols                                                       110
Chlorobenzilate                                               111
Chloroform                                                    112
Chloroprene                                                   113
Chloropropane                                                 115
Chrysene                                                      116
Cumene Hydroperoxide                                          117
DDT                                                           118
Di-tert-butyl Peroxide                                        119
Di (2-ethylhexyl) Phthalate                                    120
2,4-Diaminoanisole                                            122
Diazinon                                                      124
o-Dichlorobenzene                                             125
p-Dichlorobenzene                                             126
Dichlorobenzidine                                             127
Dichlorobutene                                                128
Dichlorodifluoromethane                                       129
1,1-Dichloroethane                                            130
Dichloronaphthoquinone                                        131
Dichlorophenol                                                132
Dichloropropene                                               133
Dichloropropionic Acid                                        134
Dichlorovinyl Dimethyl Phosphate  (Dichlorvos)                 135
Dimethylacetamide                                             136

                                83

-------
Index - Continued

Chemical

Dimethylamine
Dimethylhydrazine
Dinitrotoluene
Dioxane
Diphenyl Oxide
Disodium Methanearsonate
Dursban
Endosulfan                                                    144
Endrin                                                        145
Epichlorohydrin                                               146
Eptam                                                         147
Ethanol                                                       148
Ethylbenzene                                                  149
Ethylene                                                      150
Ethylene Dibromide                                            151
Ethylene Dichloride                                           152
Ethylene Glycol                                               153
Ethylene Oxide                                                154
Ethylenimine                                                  155
Fluoranthene                                                  156
Formaldehyde                                                  157
Guthion                                                       158
Heptachlor                                                    159
Hexachlorobenzene                                             160
Hexachlorobutadiene                                           161
Hexamethylenetetramine                                        162
Hydrazine                                                     163
Hydroquinone                                                  164
Kelthane                                                      165
Malathion                                                     166
Maleic Anhydride                                              167
Mercaptobenzothiazole                                         168
Methyl Bromide                                                169
Methyl Chloride                                               170
Methyl Ethyl Ketone                                           171
Methyl Methacrylate                                           172
4,4'-Methylene Bis(2-chloroaniline)                           173
Methylene Chloride                                            174
Methylenedianiline                                            175
Methylstyrene                                                 176
Morpholine                                                    177
Naphtha                                                       178
1-Naphthylamine                                               179
Naphthalene                                                   180
Naphthoquinone                                                181
1-Naphthyl Methylcarbamate                                    182
Nitrobenzene                                                  183
Nitrophenol                                                   184
                                84

-------
Index - Continued

Chemical                                                     Page

Nitrosodimethylamine                                          185
Nitrochlorobenzene                                            186
Parathion                                                     187
Pentane                                                       188
Pentachlorophenol                                             189
Phenol                                                        190
Polychlorinated Biphenyls                                     191
Propanol                                                      192
Propylene Oxide                                               193
Pyrene                                                        194
Sorbic Acid                                                   195
Styrene                                                       196
Sulfolane                                                     197
Tetrabromoethane                                              198
Tetrachloroethane                                             199
Tetrachloroethylene                                           200
Tetraethyl Lead                                               201
Toluene                                                       202
Toluene Diisocyanate                                          203
Toluenediamine                                                204
Toxaphene                                                     205
Trichlorfon                                                   206
Trichloroethane                                               207
Trichloroethylene                                             208
Trichlorofluoromethane                                        209
Trichlorophenol                                               210
Urethane                                                      211
Vinyl Acetate                                                 212
Vinyl Bromide                                                 213
Vinyl Chloride                                                214
Vinylidene Chloride                                           215
Xylene                                                        216
                                 85

-------
                          Acetaldehyde


Acetaldehyde is possibly a carcinogen promoter  [25] , but no refer-
ences to it as a carcinogen or mutagen were found in TOXLINE or
CANCERLINE„   Two references by Nakahara and Mori in 1939 and 1940,
as reported by Hartwell [26],  demonstrated no tumors in rats fed
acetaldehyde in their food for more than 300 days.  It is probably
not a carcinogen.
[25]  Davies,  J.  C.   Co-Carcinogenesis with respect to the Con-
     tents of Cigarette Tobacco.   R.  Soc.  Health J., 93 (6):296-
     301,  1973.

[26]  Hartwell,  J.  L.   Survey of Compounds  Which Have Been Tested
     for Carcinogenic Activity, Second Edition.  National Tech-
     nical Information Service No.  PB 216  478, 1951.


                                86

-------
                            Acetone
Acetone [2-propanone,  dimethyl ketone, Chemical Abstract Service
(CAS)  No.  67-64-1] has been extensively tested for carcinogenic
activity both by itself and as a negative solvent control for
other chemicals [5].  No significant positive results could be
found on CANCERLINE or TOXLINE for acetone.  It is also negative
on most in vitro tests and is used as a negative solvent control
for many chemicals in these tests.
                                87

-------
                          Acetonitrile
The only data suggesting that acetonitrile is a carcinogen are
equivocal results from a 2-year rat study [6].   It is considered
a noncarcinogen for this project.
                              88

-------
                            Acrolein
Acrolein appears to be toxic and reduces ciliary action of  the
bronchial epithelium  [27, 28], but it is not mutagenic in 5.
cerevisiae [29] or dominant lethal mice tests  [30].  Acrolein
has been found to be a mutagen to the TA1538 and TA98 strains
of 5.  typhimurium [31].  It will be considered to  be a possible
carcinogen for this project.

Production and Persistence

It is estimated that 6.5 x 107 kg is emitted per year, primarily
associated with acrylic acid manufacture  [1].  Other estimates
are 4.2 x 105 kg/yr released from 2.8 x 107 kg produced  [6] and
a production of 2.8 x 107 kg produced in 1974 with a 6.7% growth
forecast through 1979  [32].  It has an atmospheric half-life
estimated at 2.6 hours  [8],  Its boiling point is  -88°C and it
has a vapor pressure of 220 mm at 20°C  [33].
 [27] Shabad, L. M., et al.  The Feasibility of Preventing the
     Effects of Carcinogens on Man.  Kazan Med. Zh,  (5):92-93,
     1973.
 [28] Terrell, J. H., and  I. Schmeltz.  Cigarettes:  Chemical
     Effect of Sodium Nitrate Content.  Science, 160:1456, 1968.

 [29] Izard, C.  Mutagenic Effects of Acrolein and  its Two Epox-
     ides, Glycidol, and  Glycidal, in Saaaharomyaes Cerevisiae.
     C. R. Acad. Sci., Ser. D., 276(23):3037-3040, 1973.
 [30] Epstein, S. S., et al.  Detection of Chemical Mutagens by
     the Dominant Lethal Assay in the Mouse.  Toxicol. Appl.
     Pharmacol., 23:288-325, 1972.
 [31] Bignami, M., et al.  Relationship Between Chemical Structure
     and Mutagenic Activity in Some Pesticides:  The Use of
     Salmonella Typhimurium and Aspergillus Nidulans.  Mutat.
     Res., 46(3):243-244, 1977.

 [32] Allport, J., et al.  A Study of Industrial Data on Candidate
     Chemicals for Testing.  National Technical Information
     Service No. PB 274 264, 1977.

 [33] Verschueren, K.  Handbook of Environmental Data on Organic
     Chemicals.  Van Nostrand Reinhold Co., New York, 1977.
                                89

-------
                          Acrylonitrile


Positive Ames tests [34],  E.  coli mutation tests  [35], and viral
transformation enhancement tests (personal communication with B. C.
Casto on 9 February 1978)  have been reported along with negative
recessive lethal Vrosphila melanogaster and negative Vioia faba
chromosome aberration tests [32].  Human epidemiological evidence
points toward acrylonitrile being a carcinogen  [36].  Additionally,
a 1-year interim report from the Manufacturing Chemists Associa-
tion of ongoing ingestion and inhalation studies of acrylonitrile
in laboratory rats reports the rats developing a variety of tumors
including carcinomas [37].  Based on these findings, acrylonitrile
is being placed on the probable carcinogen list for this project.

Production and Persistence

It is estimated that 3.7 x 10s kg is emitted per year  [1].
(Another estimate is 9.6 x 106 kg per year [6].)  Acrylonitrile
has a boiling point of 77°C and a vapor pressure of 100 mm at
23°C [33].
[34] Milvey, P., and M. Wolff.  Mutagenic Studies with Acryloni-
     trile.  Mutat. Res., 48 (3-4) :271-278, 1977.

[35] Venitt, S., et al.  Mutagenicity of Acrylonitrile  (Cyano-
     ethylene)  in Escherichia Coli.  Mutat. Res., 45:283-288,
     1977.

[36] Acrylonitrile Linked to Cancer in Workers.  Chem. Eng. News,
     55:6, 1977.

[37] Finklea, J. F.  Acrylonitrile.  Am. Ind. Hyg. Assoc. J.,
     38:417-422, 1977.
                                90

-------
                             Aldrin


Aldrin has been found to cause neoplasia in two strains of mice
[38]  and tumors in weanling rats  [39].  Aldrin is converted into
dieldrin in the environment [40], and dieldrin is a carcinogen at
0.1 ppm in dietary exposure to mice  [41].  Thus the sale and pro-
duction of aldrin was suspended [42].  Many other animal studies
have been conducted with questionable results  [43], and some
in vitro tests have been negative [18].  Since there are enough
data to suspend production of aldrin, it will be considered a
probable carcinogen for this project.

Production and Persistence

It is estimated that 4.5 x 106 kg aldrin were produced in 1971
[43].  Another production estimate is 1.1 x 107 kg/year  (1976)  [6].
 [38] Song, J., and W. E. Harville.  Carcinogenicity of Aldrin and
     Dieldrin on Mouse and Rat Liver.  Fed. Proc., 23:336, 1964.

 [39] Diechmann, W. B., et al.  Tumorigenicity of Aldrin, Diel-
     drin, and Endrin in the Albino Rat.  Ind. Med Surg., 39(10):
     426-434, 1950.
 [40] Wurster, C. F.  Aldrin  and Dieldrin.  Environment,  13(8):
     33-45, 1971.
 [41] Epstein, S. S.  Prevention - Environmental  Exposure:  An
     Overview, Including the Role of Pesticides.  Third  Inter-
     national Symposium on Detection and Prevention of Cancer,
     1976.  p. 5.
 [42] Epstein, S. S.  Case Study 5:  Aldrin and Dieldrin  Suspen-
     sion Based on Experimental Evidence and Evaluation  and
     Societal Needs.  Ann. N.Y. Acad.  Sci., 271:187-195,  1976.

 [43] IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 5, 1974.  pp. 25-38.
                                 91

-------
                         Allyl Chloride


Allyl chloride (3-chloropropene, CAS No. 107-05-1) is on the
NIOSH Safety Alert List.  No references have been found on
TOXLINE, CANCERLINE, or in the Stanford Research Institute study
on hazard priority ranking [7],  to indicate that allyl chloride
is a carcinogen or mutagen.  A recent reference, however, reports
that allyl chloride is a mutagen in S.  typhimurium, S. eeTevisiae,
and E.  coli test systems [9].   It is therefore classified as a
possible carcinogen for this project.

Production and Persistence

It is estimated that 4.2 x 105 kg is emitted per year from
stationary sources  [1].  Another estimate is 2 x 106 kg released
from a production of 1.3 x 108 kg per year  [44], and a production
estimate of 1.3 x 108 kg in 1972 [6],  It is reported to take
27 minutes for 50% of the allyl  chloride in a 1-ppm solution to
evaporate at 25°C [33].  It has  a half-life with HO radical of
21 hours and with 03 radicals  of 9 hours, and it hydrolyzes with
a half-life of 7 days [44].  It  has a boiling point of 45°C, a
vapor pressure of 340 mm at 20°C, and a solubility of 3.3 g/1  [33].
[44]  Brown,  S.  L.,  et al.   Research Program on Hazard Priority
     Ranking of Manufactured Chemicals.  National Technical
     Information Service No. PB 263 164,  1975.
                                92

-------
                             Aniline
The IARC monograph on aniline  [45] reports that aniline is prob-
ably not a carcinogen and that what early researches believed
was cancer from aniline was most likely due to impurities such
as benzidine.  It has tested negative on a differential growth
E. Goli test (pol A) [46] and on S. typhimurium strains TA1535,
1537, 100, and 98 with and without microsomes  [32],  It has also
been reported negative in reversion to prototrophy in Aspergillus
nidulans  (meth3~) and several other tests [32].  It was classi-
fied negative/inadequate in one of the latest reviews  [32] and
will be considered a probable noncarcinogen for this project.
 [45] IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 4, 1974.  pp. 27-36.
 [46] Fluck, E. R., et al.  Evaluation of a DNA Polymerase-
     Deficient Mutant of E. Coli for the Rapid Detection of
     Carcinogens.  Chem. Biol. Interact., 15:219-231, 1976.
                                93

-------
                           Anthracene
Anthracene is on the NIOSH Suspected Carcinogen List because of
two 1955 references.  In the first one [47], anthracene was
found to be noncarcinogenic orally and interpertioneally.  But
when injected in 550 doses over a 2- to 3-year period  (6 times/
week - total dose 4.5 g/rat),  5 out of 9 rats developed local
fibrosarcomas.   It is now known that multiple injections can
sometimes cause fibrosarcomas.   Recent studies [48] have shown
anthracene to be a noncarcinogen and it is presently being used
as a noncarcinogenic standard  on studies to develop short-term
assays for carcinogens [49-52].
 [47] Schmall, D.  Prufung von Naphthalin and Anthracen auf Car-
     cerogene Wirking an Ratten.  Zeitschrift fur Krebsforschung,
     60:697-710, 1955.

 [48] Stanton, M. F., et al.  J. Natl.  Cancer Institute, 49(3):
     867-877, 1972.

 [49] Pienta, R. J., et al.  Morophological Transformation of
     Early Passage Golden Syrian Hamster Embryo Cells Derived
     from Cryopreserved Primary Cultures as a Reliable in Vitro
     Bioassay for Identifying Diverse Carcinogens.  Int. J-
     Cancer, 19:642-655, 1977.

 [50] DiPaolo, J. A., et al.  Quantitation of Chemically Induced
     Neoplastic Transformation of BALB/3T3 Cloned Cell Lines.
     Cancer Research, 32:2686-2695, 1972.

 [51] Purchase, I. F. H., et al.  Evaluation of Six Short-Term
     Tests for Detecting Organic Chemical Carcinogens and Recom-
     mendations for Their Use.  Nature, 264:624-627, 1976.

 [52] McCann, J., et al.   Detection of Carcinogens as Mutagens in
     the SalmoneI la/Microsome Test, Assay of 300 Chemicals.
     Proc. Natl. Acad. Sci. (USA), 72:5135-5139, 1975.


                                94

-------
                        Benz (a)anthracene


Benz(a)anthracene (1,2-benzanthracene, CAS No. 56-55-3) is well
known as a carcinogen.  It is carcinogenic orally, subcutaneously
and topically for mice [53],  It is one of the standard carcino-
gens used to evaluate the validity of short-term tests and will
be considered a probable carcinogen for this project.

Production and Persistence

It is estimated that less than 100 kg/year is emitted from carbon
black furnaces, the only stationary source cited for this chemi-
cal [1].  It is emitted in the exhaust from gasoline engines
(61.7 mg/kg exhaust tar)  and diesel engines  (2.3-15 yg/m3 exhaust)
[53].  It has been detected  in the air, soil, food, and cigarette
smoke condensate  [53].  It has a boiling point of 400°C [53].
 ^53] IARC Monographs:  Evaluation of  the Carcinogenic  Risk  of
     Chemicals to Man, Volume  3, 1973.  pp.  45-68.
                                95

-------
                             Benzene


Benzene (CAS No.  71-43-2)  is one of the industrial substances sus-
pected of carcinogenic potential to man as listed by the American
Conference of Governmental Industrial Hygienists  [54], and it will
soon be controlled as a carcinogen.  The International Agency for
Research on Cancer [55] reports animal data which "do not permit
the conclusion that carcinogenic activity has been demonstrated."
In human data they support a relationship between exposure to
benzene or benzene mixtures and the development of leukemia.
Along with some positive studies [56], many references occur in
the literatuare where benzene is a negative solvent control in
animal studies [5].   In spite of these references, it is believed
that benzene induces chromosomal damage in animals and man [32]
and is a known carcinogen.  An assessment of the air pollution
aspects of benzene has been conducted [57].  Since benzene is
being controlled as a carcinogen, it will be considered a probable
carcinogen for this project.

Production and Persistence

It is estimated that 1 x 108 kg benzene is emitted per year, with
solvent evaporation from degreasing operations contributing over
70% of the total  [1].  Another estimate is 4 x 107 kg per year
released from commercial uses of benzene [56].  It reacts rapidly
with HO (tjg = 3 days) but slowly with RO2 and O3 and has a 12.5
log partition coefficient  [56].  Its boiling point is 80.1°C and
it has a vapor pressure of 76 mm at 20°C [33].
[54]  TLVs® Threshold Limit Values for Chemical Substances and
     Physical Agents in the Workroom Environment with Intended
     Changes for 1977.   American Conference of Government Indus-
     trial Hygienists,  1977.

[55]  IARC Monographs:   Evaluation of the Carcinogenic Risk of
     Chemicals to Man,  Volume 7, 1974.  pp. 203-222.

[56]  Brown,  S. L. ,  et al.   Research Program on Hazard Priority
     Ranking of Manufactured Chemicals.  National Technical
     Information Service No. PB 263 162, 1975.

[57]  Walker, P.  Air Pollution Assessment of Benzene.  National
     Technical Information Service No. PB 256 734, 1976.
                                96

-------
                            Benzidine
Benzidine is reported to be carcinogenic in the mouse, rat,
hamster,  and possibly in the dog [58],  Given orally, it has pro-
duced bladder carcinoma in the dog after a long latent period and
liver tumors in the rat and hamster.  Benzidine was a carcinogen
to mice when given either by stomach intubation or in food  [59].
These references, along with many others in TOXLINE and CANCERLINE
show that benzidine should be considered a probable carcinogen.

Production and Persistence

It is estimated that 4.7 x 106 kg is produced per year [6].  A
release factor of 0.015 is assumed which would give 7 x 10^ kg
released per year.  This is probably too high since benzidine is
well known as a carcinogen.  Perhaps 7 x 103 kg would be closer
to reality-  It reacts with OH and O3 with a t^ of 1 day  [60].
It has a boiling point of 402°C  [33] and can be sublimed  [58].
 [58] IARC Monographs:  Evaluation of  the Carcinogenic Risk of
     Chemicals to Man, Volume 1, 1972.  pp.  80-86.
 [59] Vesselinovitch, S. D., et al.  Factors  Modulating  Benzidine
     Carcinogenicity Bioassay.  Cancer Res.,  35(10) :2814-2819 ,
     1975.

 [60] Brown, S. L., et al.  Research Program  on Hazard Priority
     Ranking of Manufactured Chemicals.  National Technical
     Information Service No. PB 263 163, 1975.
                                 97

-------
                         Benzo(a)pyrene


Benzo(a)pyrene (3,4-benzpyrene,  CAS No. 50-32-8) is well-
established carcinogen following many different administrations
including oral, skin, subcutaneous and intratracheal routes  [61].
Positive results have been reported with mice, rats, guinea pigs,
monkeys, newts, hamsters, and ducks [61].  It will be considered
a probable carcinogen for this project.

Production and Persistence

Although not manufactured in quantity, it is a byproduct of com-
bustion.  It is estimated that 8.3 x 105 kg per year is released
from stationary sources, with 96% of this coming from:   (1) coal
refuse piles, outcrops and abandoned mines, (2) residential ex-
ternal combustion of bituminous  coal,   (3) coke manufacture, and
(4) residential external combustion of anthracite coal  [1].  It
has a boiling point of 311°C at  10 mm and 475°C at 760 mm  [61].
;61]  IARC Monographs:   Evaluation of the Carcinogenic Risk of
     Chemicals to Man,  Volume 3,  1973.  pp. 91-136.
                                98

-------
                     Benzoquinone  (Quinone)


Japanese references from 1940 [62] and 1941  (as reported in
Reference 5)  state that 3/87 mice painted with benzoquinone  (in
benzene) developed skin cancer with 9/87 papillomas after 200 days
compared to 0/46 skin cancers and 1/46 papillomas for the benzene
control.  Skin painting with a benzene solution in 1953 was said
to cause 16/80 ear duct carcinomas [63].  In 1954 an 1956, inha-
lation experiments with a total of 50 treated mice were conducted
with negative results [64].   By subcutaneous injection, 24 rats
were tested with negative results in 1957  [64].

More recent references show that benzoquinone does not decrease
hatchability of the Drosophila melanogaster  [65], is not mutagenic
toward Drosophila or cultured human leukocytes [65], produces no
increase in recessive sex-lined lethan mutations in Drosophila,
and did not significantly alter the rate of chromated transloca-
tions or breaks in leukocytes [66].  No other significant data
were found in TOXLINE, CANCERLINE, or Reference 5.  Benzoquinone
is therefore to be considered a probable noncarcinogen for this
project.
 [62] Takizawa, N.  On the Carcinogenic Action of Certain Quinones
     Proc. Imperial Acad. (Tokyo), 16:309-312, 1940.

 [63] Tiedmann, H.  Ztschr. Naturforsch., 8b:49-50, 1953.
 [64] IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 15, 1977.  pp. 255-264.

 [65] Vogel, E.  Differential Sensitivity of Immature and Mature
     Oocytes of Drosophila Melanogaster to the Induction of
     Dominant Lethals Following Treatment of Mono- and Polyfunc-
     tional Aziridine Analogues.  Mutat. Res., 14:250-253, 1972.

 [66] Lueers, H., and G. Obe.  Possible Mutagenic Activity of
     p-Benzoquinone.  Mutat. Res., 15:77-80, 1972.


                                99

-------
                        Benzoyl Peroxide


Benzoyl peroxide (CAS No. 94-36-0)  was extensively tested in
mice and rats between 1962 and 1967 by 6 authors on more than
1,100 animals [5].   Benzoyl peroxide is on the NIOSH Suspected
Carcinogen List because in one of these studies, 1/30 mice devel-
oped a squamous papilloma after application of benzoyl peroxide
in benzene to the skin.  No recent mutagen or carcinogen refer-
ences could be found on TOXLINE or CANCERLINE.  It has been found
negative in a dominant lethal mouse test,  on an E.  coli (pol A)
mutagen test, and a Micrococcus pyogenes test [32].  There is
very little doubt that benzoyl peroxide should be considered a
noncarcinogen.
                               100

-------
                         Benzyl Chloride


Benzyl chloride (a-chlorotoluene, CAS No. 100-44-7) has been
found positive on a differential growth E. ooli  (pol A) mutagen
test [46].   It is also positive on a subcutaneous rat test at
2.1 g/kg (51 weeks) in 3/14 rats and at 3.9 g/kg in 6/8 rats  [67].
It is weakly mutagenic in S. typhimurium tests at 2 mg/plate  [68],
and is considered carcinogenic in rats by the IARC  [67] .  It is
considered a probable carcinogen for this project.

Production and Persistence

In 1972 it was estimated that 3.6 x 107 kg was produced with
65-70% of this going towards the manufacture of butyl phthalate
and 30-35% towards other organic products [67].  Production has
been estimated at 4.5, 3.2 and 4.1 x 107 kg in 1974, 1975 and
1976 and is predicted to grow at 5-7% per year through 1980 [32].
It has a boiling point of 179°C and vapor pressure of 1 mm at
22°C [33].
 [67] IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 11, 1976.

 [68] McCann, J., et al.  Detection of Carcinogens as Mutagens:
     Bacterial Tester Strains with R Factor Plasmids.  Proc. Nat
     Acad. Sci  (USA), 72:979-983, 1975.

                                101

-------
                            Biphenyl


There is one reference which shows subcutaneous biphenyl (diphenyl,
CAS No.  92-52-4)  to induce an excess of tumors in mice  [69],  No
supporting references could be found in CANCERLINE or TOXLINE.
Biphenyl is therefore placed on the possible carcinogen list for
this project.

Production and Persistence

It is estimated that 9.2 x 104 kg biphenyl is emitted per year
from the manufacture of polychlorinated biphenyls  [1].  Since
the production of polychlorinated biphenyls has been stopped,
this source of biphenyl emissions has probably ceased to exist.
It has a boiling point of 254°C  [33].
 [69] Evaluation of Carcinogenic, Teratogenic, and Mutagenic
     Activities of Selected Pesticides and Industrial Chemicals,
     Volume I.  National Technical Information Service No. PB  223
     159, 1968.
                                102

-------
                     Bis(chloromethyl) Ether


Bis(chloromethyl)  ether (BCME, dichloromethyl ether; CAS No.
542-88-1)  is carcinogenic to mice following inhalation, skin
application and subcutaneous administration [70].  It is also
carcinogenic to rats by inhalation and subcutaneous administra-
tion [70].  Epidemiological data suggest it is also a human
carcinogen  [70].  It is being regulated as a carcinogen and will
be considered a probable carcinogen for this project.

Production and Persistence

It is estimated that less than 100 kg BCME is emitted per year
[1].  A primary source of emissions is the production of poly-
methylene polyphenyl isocyanate  [1].  Its production in 1974 was
estimated to be less than 450 kg [8].  In water the half-life of
BCME is 38 seconds and in the air  (50% relative humidity) its
half-life is 25 minutes [8].  It has a boiling point of 104°C  [8;
 [70] IARC Monographs:  Evaluation of the Carcinogenic  Risk of
     Chemicals to Man, Volume 4, 1974.  pp.  231-238.
                                103

-------
                           Butadiene
1,3-Butadiene (CAS No.  106-99-0)  has not been extensively tested
for mutagenicity or carcinogenicity.  No references could be
found on TOXLINE,  CANCERLINE,  or in the seven collected volumes
of Reference 5 on tests conducted, although there is interest in
a possible relationship between styrene-butadiene rubber plants
and neoplasms of the lymphatic and hematopoietic tissue [71].
Butadiene will be considered a probable noncarcinogen for this
project.
[71]  Smith,  A.  H.,  and L.  Ellis.   Styrene Butadiene Rubber Syn-
     thetic  Plants  and Leukemia  (Letter to Editor).  J.  Occup
     Med.,  19(7):441,  1977.
                               104

-------
                             Captan


Captan has been found to be a potent mutagen, in both prokaryote
and eukaryote test systems too numerous to list.  It has also
been found to produce hepatomas in mice [69].  Because of the
many positive mutagenicity tests along with a marginally positive
mouse carcinogenicity test, captan has been placed on the probable
carcinogen list.

Production and Persistence

It is estimated that less than 100 kg per year of captan is
emitted [1].    (Another estimate is production of 8.1 x 106 kg
per year with 0.01 released, or 8 x 10^ kg per year emitted  [6].)
                               105

-------
                        Carbon Disulfide
There is nothing in TOXLINE or CANCERLINE to indicate that carbon
disulfide is a carcinogen or a mutagen.  One industrial epidemio-
logical study showed carbon disulfide to have no correlation with
incidence of cancer [72] .
[72]  DiVito, G.,  and G. L. Sommi.   The Incidence of Infectious
     Diseases, Hemopathies, and Neoplasms in Workers Exposed  to
     Carbon Disulfide.  Folia Med.  (Napoli) , 46 (11) :972-979 ,  1963
                                106

-------
                      Carbon Tetrachloride
Carbon tetrachloride  (tetrachloromethane, CAS No. 56-23-5) has
been reported to produce liver tumors in the mouse, hamster, and
rat following administration by inhalation and oral ingestion
[73].  It was not a mutagen as tested by several microbial sys-
tems  [32].  Carbon tetrachloride is considered a probable carci-
nogen for this project.

Production and Persistence

It is estimated that  1.2 x 107 kg of carbon tetrachloride is
emitted per year  [1].  Another estimate is a production of
4.5 x 108 kg with 2.7 x 107 kg released  [7].  A document is avail-
able on the air pollution assessment of carbon tetrachloride [74],
Estimates of carbon tetrachloride production include 4.5 x 108 kg
 (1970)  [73], 4.8 x 108 kg  [6], 7.3 x 108 kg  (1974)  [8] and 5.3,
4.1, and  3.8 x 10s kg for 1974, 1975, and 1976  [32].   It is fore-
cast that the 1975-1976 decline will continue.  The half-life of
carbon tetrachloride  in the water is about 70,000 years  [7], and
in the troposphere it is about 10 years  [8].  It is estimated to
have a half-life of 10-33 weeks toward atmospheric photodegrada-
tion  [74].  The boiling point of carbon tetrachloride  is 76.7°C,
and  it has a vapor pressure of 90 mm at 20°C  [33].  For a review
of its production, uses and biological activity, see the Fishbein
article  [75] .
 [73]  IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals  to  Man,  Volume 1,  1972.   pp.  53-60.

 [74]  Johns,  R.  Air  Pollution Assessment of  Carbon  Tetrachloride.
      National Technical Information Service  No.  PB  256 732,  1976.

 [75]  Fishbein,  L.  Industrial Mutagens  and Potential Mutagens,  I.
      Halogenated Aliphatic  Derivatives.   Mutat.  Res., 32:267-308,
      1976.


                                107

-------
                        Chloracetic Acid


Chloracetic acid (monochloroacetic acid, CAS No. 79-11-8) has
been reported as being carcinogenic in mice when injected sub-
cutaneously at 100 mg/kg [2].   The primary reference, however,
does not report a statistical  difference in tumors; data reported
for the test mice are not much different from those for the
control mice [69].   In other tests, Chloracetic acid was negative
when given to 6 rats as 0.005-0.1% of their diet for 208 days
[76] and negative when given at 46.4 mg/kg in the water of 72
mice for days 7-28 followed by 149 ppm in their diet for another
17 months [77].  It has also been found nonmutagenic by B.  subtilis
[78] and S.  typhimurium [78-81]  tests in vitro.  All of these
demonstrate that Chloracetic acid is not a mutagen nor a
carcinogen.
[76]  Fuhrman,  F.  A.,  et al.   Arch.  Inst.  Pharmacodym.,  102:113-
     125,  1955.

[77]  Innes,  J.  R.  M.,  et al.   J.  Nat.  Cancer Inst.,  42:1101-1114,
     1969.

[78]  Elmore,  J.  D.,  et al.  Vinyl Chloride Mutagenicity via the
     Metabolites  Chlorooxirane and Chloroacetaldehyde  Monomer
     Hydrate.   Biochem.  Biophys.  Acta,  442:409-419,  1976.
[79]  Rannug,  U.,  et  al.   The  Mutagenicity of Chloroethylene
     Oxide,  Chloroacetaldehyde,  2-Chloroethanol and  Chloroacetic
     Acid,  Conceivable Metabolites of  Vinyl Chloride.   Chem.
     Biol.  Interact.,  12(3-4):251-263,  1976.

[80]  Bartsch,  H.,  et  al.  Human,  Rat and  Mouse-Liver Mediated
     Mutagenicity  of  Vinyl Chloride in 5.  Typhimuvium  Strains.
     Int.  J.  Cancer,  15 (3) :429-437, 1975.

[81]  Malaveille,  C.,  et al.   Mutagenicity of Vinyl Chloride,
     Chloroethyleneoxide, Chloroacetaldehyde and Chloroethanol.
     Biochem.  Biophys.  Res. Comm.,  63 (2) :363-370,  1975.


                               108

-------
                            Chlordane
Chlordane has been found to be a carcinogen to mice in a study
conducted by the National Cancer Institute  [82] .  It is also a
mutagen in tests like the enhancement of viral transformation
(personal communication with B. C. Casto on 9 February 1978).
It is considered a probable carcinogen for this project.

Production and Persistence

It is estimated that 1.1 x 107 kg per year of chlordane is
produced  [6] .
 !82] Bioassay of Chlordane  for Possible Carcinogenicity  (CAS No.
     57-74-9.  National Technical  Information  Service No. PB 271
     977.


                                109

-------
                            Cresols
Cresols (primarily o-cresol)  have been shown to be promoters of
carcinogenicity when given with initiators such as 3,4-benzpyrene
(Kaiser),  dimethylbenzanthracene [83]  or in complex mixtures [84,
85].   On the other hand,  normal adults excrete about 30 mg of
volatile phenols per day of which 90%  is p-cresol [86].  Thus,
cresols are probably not carcinogens but could be promoters.
 [83] Bakke, 0. M.,  and T. Midtvedt.   Influence of Germ-Free Status
     on the Excretion of Simple Phenols of Possible Significance
     in Tumor Promotion.  Experimentia, 26 (5):519, 1970.

 [84] Bock, F. G., et al.  Composition Studies on Tobacco.  XLIV.
     Tumor-Promoting Activity of Subfractions of the Weak Acid
     Fraction of Cigarette Smoking Condensate.  J. Nat. Cancer
     Inst., 47 (2) :429-436, 1971.

 [85] Shustova, M. N., and L. N. Samiolovich.  Blastomogenicity of
     Neutralized Soots from the Sulfate Shop of a Coke Plant.
     Gig. Sanit., 36 (7) :103-104, 1971.

 [86] Bone, E. S., et al.  The Production of Urinary Phenols by
     Human Gut Bacteria,  (Meeting Abstract).  J. Med. Microbiol.,
     9(2):vi, 1976.


                                110

-------
                         Chlorobenzilate
Chlorobenzilate (CAS No. 510-15-6) has been found to produce hepa-
tomas in mice when administered orally [69,77,87] and is listed
by the U.S.  Commission on Pesticides and Their Relationship to
Environmental Health as a group B chemical (positive results in
one or more animal species at 0.01 significance level [88]).
Several short-term tests have been negative for Chlorobenzilate
[18].  For this project, it is considered a probable carcinogen.

Production and Persistence

A 1976 reference [6] cites a production of 9 x 10s kg per year,-
and it is said [87]  that the 1971 production was 1 x 106 kg.
[87] IARC Monographs:  Evaluation of the Carcinogenic Risk of
     Chemicals to Man, Volume 5, 1974.  pp. 75-81.
[88] Jurek, A.  Carcinogenicity of Pesticides.  Roczn. Panstw.
     Zakl. Hig., 25 (5):563-576 , 1974.
                                Ill

-------
                           Chloroform
Some of the current literature [89-92] indicates that chloroform
is a carcinogen.   Even though more data are required before a
final determination is made, the positive data on mice and rats
suggest that chloroform be placed on the probable carcinogen list
for this project.

Production and Persistence

It is estimated that 1 x 106 kg chloroform is emitted per year
[1].  Another estimate is 1.7 x 107 kg per year  [60] emitted.
Production estimates are 1.3 x 10s kg per year [8], 1.1 x 10s  [6],
and 1.1 x 108 kg per year [89].  About 96% of production is con-
verted to chlorodifluoromethane.   In the troposphere chloroform
degrades slowly with a 10-year half-life [8].  It reacts with HO
radical with a tJ^ of 13 hours  [8] and hydrolyzes with a t^ of
3,000 years  [8,60].  The log partition coefficient is 1.97 for
chloroform [60].   It has a vapor pressure of 160 mm at 20°C and
a boiling point of 62°C [33].  It takes only 18-25 minutes to
evaporate 50% of the chloroform from a 1-ppm solution at 25°C
[33].
[89]  IARC Monographs:   Evaluation of the Carcinogenic Risk of
     Chemicals  to Man,  Volume 1,  1972.   pp.  61-65.

[90]  Powers,  M.  B.,  and R.  W. Yoelker.   Evaluation of the Onco-
     genic Potential of Chloroform by Long-Term Oral Administra-
     tion in  Rodents (Meeting Abstract).  Toxicol.  Appl. Pharmacol. ,
     37:179,  1976.

[91]  Renne, R.  A.,  et  al.   Pathology of Long-Term Oral Adminis-
     tration  of Chloroform in Rodents (Meeting Abstract).  Toxo-
     col.  Appl.  Pharmacol.,  37:179-180,  1976.

[92]  Chloroform Tagged  as  Carcinogen in Mice.   Chem. Eng. News,
     54:6,  1976.


                                112

-------
                           Chloroprene


Chloroprene (2-chloro-l,3-butadiene, CAS No. 126-99-8) although
known to be toxic was not considered to be a suspected carcino-
gen until three Russian papers linked occupational exposure of
Chloroprene to skin and lung cancers  [93-95].  Since that time,
a short-term viral enhancement [96] test at  125 yg/ml  (personal
communication with B. C.  Casto on 9 February 1978) and S. typhi-
murium  (Ames)  tests  [97]  have been positive, while long-term rat
and mouse studies have been negative  [98,99].  A review  of health
records and death certificates for DuPont Corporation employees
exposed to Chloroprene convinced investigators that no excess
of any disease similar to that seen for vinyl chloride had been
observed  [100].  However, some increase in lung cancer has been
seen this population  [100].  Chloroprene has also been found to
accelerate the growth of transplanted Crocker murine sarcoma in
the rat  [44].   Thus, it lies on the border between a possible
and a probable carcinogen.  It will be classified as a possible
carcinogen for this project.

Production and Persistence

It is estimated that 7.5 x 106 kg Chloroprene is emitted per
year  [1].  Another estimate is 2.7 x 106 kg/year released [44].
Some estimates of production are about 1.8 x 10s kg/year  [6,44],
1.6 x 10s kg/year  [8], and 1.8 x 10s kg and  1.6 x 108 kg in 1974
and 1975, with 4% annual growth predicted through 1981  [32].
Because of its low solubility and high volatility, it will soon
migrate to the atmosphere  [8].  In the atmosphere it is  said to
have an atmospheric half-life of less than 10 hours because of
OH radical reaction  [8].  Its boiling point  is 59.4°C and it has
a vapor pressure of  200 mm at 20°C  [33] .
 [93] Khachatryan, E. A. The Role of Chloroprene in the Process
      of Skin Neoplasm Formation.  Gig. Tr. Prof. Zabol., 16:54-
      55, 1972.
 [94] Khachatryan, E. A.  The Occurrence of Lung Cancer Among
      People Working with Chloroprene.  Problems in Oncology,
      18:85, 1972.
 [95] Khachatryan, E. A.  Lung Cancer Incidence Among Chloroprene
      Handling Workers.  Yopr. Onkol., 18:85-86, 1972.

 [96] Casto, B. C., et al.  Assay of  Industrial  Chemicals  in  Syrian
      Hamster Cells for Enhancement of Viral Transformation.
      Proc.  Am. Assoc. Cancer Res., 18:155, 1977.

 [97] Bartsch,  H., et al.  The Predictive Value of Tissues-Mediated
      Mutagenicity Assays to Assess the Carcinogenic Risk of
      Chemicals.  IARC Sci.  Pub.  No. 12, 1976.  pp. 467-491.


                                 113

-------
Chloroprene
References - Continued
  [98]  Zilfyan, V. N., et al.  Experimental  Study  of  Chloroprene
       for Carcinogenicity.  Yopr. Onkol., 23:61-65,  1977.
  [99]  Zilfyan, V. N., et al.  Results  of  a  Study  of  Chloroprene
       for Carcinogenicity.  Zh. Eksp.  Klin.  Med.,  15:54-57,  1975,
 '100]  Lloyd, J. W.  Cancer Risks Among Workers  Exposed to  Chloro-
       prene.  Ann. N.Y. Acad. Sci.,  271:91-93,  1976.


                                114

-------
                          Chloropropane


No reference to carcinogenic or mutagenic action of chloropropane
could be found in TOXLINE, CANCERLINE, or any of the other refer-
ences consulted.   It is probably a noncarcinogen and will be con-
sidered as such for this project.
                               115

-------
                            Chrysene


Chrysene [benzo(a)phenanthrene,  CAS No. 218-01-9] is fairly well
established as a weak carcinogen.  It has produced skin tumors in
mice following repeated painting, and 2-20 mg injected subcutane-
ously in mice produced tumors after a long induction period  [101],
It is also a mutagen causing 167 revertants per microgram  [52].
It is considered a probable carcinogen for this project.

Production and Persistence

Although chrysene is not a manufactured chemical, it is a product
of combustion found widely dispersed in the environment.  In one
test of automobile exhaust, 12 yg was found after 1 minute of
operation  [101].  In the atmosphere, 150-490 yg chrysene has
been found per gram organic particulate matter [101].   It has a
boiling point of 488°C [33] .
 [101] IARC Monographs:  Evaluation of the Carcinogenic  Risk  of
      Chemicals to Man, Volume 3, 1973.  pp.  159-177.
                               116

-------
                      Cumene Hydroperoxide


Cumene hydroperoxide (dimethylbenzyl hydroperoxide) is cited as
being a carcinogen but at 34 and 90 mg/kg did not  induce satis-
tically significant dominant lethal effects in mice  [30, 102].
Cumene hydroperoxide is said to cause neoplasms in mice both by
inhalation at 304 mg/kg [103] and subcutaneously at 10 g/kg  [104]
On the basis of the two animal studies, it is considered a possi-
ble carcinogen for this project.

Production and Persistence

It is estimated  [8] that the 1974 production was 1.4 x 109 kg.
Another estimate of production  [6] is 9.1 x 108 kg per year with
a production loss factor of  0.015, or 1.3 x 107 kg/year.  It has
a vapor pressure of 1 mm at  70°C  [6].  Because of  its low volatil-
ity and moderate solubility  in water, it is not likely to remain
in the atmosphere  [8].  Photochemical and HO radical reactions
are likely pathways for transformation of peroxides in the atmos-
phere with a half-life of less than a few hours [8].
 [102] Epstein,  S.  S.,  and  H.  Shafner.   Chemical  Mutagens in the
      Human Environment.   Nature,  219:385-387,  1968.

 [103] Radiation Research,  Supplement 3:193,  1963 (as  cited in
      Reference 2).
 [104] J. Nat. Cancer  Inst., 37:825,  1966  (as  cited  in  Reference  2)
                                 117

-------
                               DDT
DDT [1,1,l-trichloro-2,2-di-(4-chlorophenyl) ethane, CAS No.
50-29-3]  has both positive and negative -In vivo and in vitro
data.   It was negative in feeding studies of dogs and monkeys
[105]  and in a differential growth E.  coli  (pol A) mutagen test
[46].   Given orally,  it produced liver cell tumors in several
strains of mice,  and some of its metabolites produced lung tumors
in mice [46].  It is positive in a recessive lethal Drosophila
test [106].   All  things considered, it is probably a carcinogen
and will be classified as one for this project.

Production and Persistence

In 1971,  2 x 107  kg was the estimated production  [105].  In 1971
it was found in the air in concentrations of 0.1 ng/m3 to 1.56
jjg/m3 .   The soil  half-life is estimated to be 15 years [105].
It has a vapor pressure of 1.9 x 10~7 mm at 20°C and a melting
point  of 74°C.
[105]  IARC  Monographs:   Evaluation  of  the  Carcinogenic Risk of
      Chemicals  to  Man,  Volume  5, 1974.  pp.  83-124.

[106]  Vogel,  E.   The  Relation Between  Mutational Pattern and
      Concentration by Chemical Mutagens in Drosophila.  IARC
      Sci.  Pub.  No. 12,  1976.   pp.  117-137.
                               118

-------
                     Di-tert-butyl Peroxide


Di-tert-butyl peroxide  [bis(1,1-dimethylethyl) peroxide, CAS No
110-05-4]  has been found to induce malignant lyraphomas in 7/35
mice which inhaled 100 ug/m3 of this chemical  [107].   (Tert-butyl
hydroperoxide has also been found negative by  skin  application
tests on mice [109, 110].)  Di-tert-butyl peroxide  is on a list
of "suspected carcinogens" studied for environmental fate [8].
Since the positive mice test results were by the inhalation
route, which has fewer false positives than does injection, di-
tert-butyl peroxide will be considered a possible carcinogen for
this project.  Considering the type and date  (1963) of the posi-
tive tests, however, negative short-term in vitvo mutagenicity
data would probably change its classification  to a  probable non-
carcinogen by the criteria used for this project.

Production and Persistence

Production is estimated to be 3 million pounds per  year  [8].  It
is only slightly volatile but moderately soluble in water.  Thus
most of the di-tert-butyl peroxide will remain in the water sys-
tem.  In the water the presence of >1 ppm Fe2+ and Mn2+ leads to
decomposition to acids and alcohols with t^ <10 hours  [8],  In
the atmosphere photochemical and HO radical decomposition leads
to a tjg of 79 hours  [8] .
 [107] Kotin, P-, and H. L. Falk.  Radiation Research Supplement
      3:193-211, 1963  (as cited in Reference  5).

 [108] Saffioti, U., and P- Shubik.  Nat. Cancer Inst. Monog.,
      10:489-507, 1963  (as cited in Reference  5).

 [109] Hoshing, H., et al.  Gann 61 (2):121-124, 1970  (as cited  in
      Reference 5) .

 [110] Van Duuren, B. L., et al.  J. Nat. Cancer Inst., 39:1217-
      1228, 1967  (as cited in Reference 5).
                                .119

-------
                   Pi (2-ethylhexyl)  Phthalate


Di (2-ethylhexyl)  phthalate (DEHP, dioctyl phthalate, OOP; CAS No.
117-81-7)  is a high-volume plasticizer which had in the past been
considered virtually nontoxic as judged by various acute and
chronic tests [111].   Although early animal tests  (dog, guinea
pig, rat)  were negative [112],  at least one source  [6] now cites
neoplastic effects in rats orally given 43.2 g/kg  (96 weeks)
di (2-ethylhexyl)  phthalate.  Although this dose is rather high,
there are  also several references which show this chemical to
be both mutagenic and teratogenic [113-121].  It is therefore
classed as a possible carcinogen for this project, at least until
a carcinogen bioassay being conducted under NCI contract [122] is
concluded  and reported.

Production and Persistence

It is estimated that 2.6 x 105 kg DEHP is emitted per year from
stationary sources [1].  Other estimates are 2.0 x 10s kg pro-
duced and  released [60] and 1.8 x 10s kg produced in 1974 [6],
It is said to biodegrade rapidly in water and sludge  [123].

In the air it reacts with the HO radical with a half-life of 1
day  [60].   It has a boiling point of 385°C and a vapor pressure
of 1.2 mm  at 200°C [33].
[Ill] Documentation of the Threshold Limit Values for Substances
      in Workroom Air.  American Conference of Governmental In-
      dustrial Hygienists, 1976.  pp. 96-97.

[112] Shubik, P., et al.  Survey of Compounds Which Have Been
      Tested for Carcinogenic Activity, Supplement I.  National
      Technical Information Service No. PB 216 248, 1957.

[113] Singh, A. R.,  et al.  Mutagenic and Antifertility Sensitiv-
      ities of Mice to Di-2-ethylhexyl Phthalate  (DEHP) and
      Dimethoxyethyl Phthalate  (DMEP).  Toxicol. Appl. Pharmacol.,
      29(l):35-46, 1974.

[114] Mathur, S. P.   Respirometric Evidence of the Utilization of
      Dioctyl and Di-2-ethylhexyl Phthalate Plasticizers.  J.
      Environ. Qual., 3(3):207-209, 1974.

[115] Peakall, D. B.  Phthalate Esters:  Occurrence and Biological
      Effects.  Residue Reviews, 54:1-41, 1975  (177 references).

[116] Recent Progress in Safety Evaluation Studies on Plasticizers
      and Plastics and Their Controlled Use in Japan.  Environ.
      Health Perspec., 17:203-209, 1976.
                               120

-------
Di (2-ethylhexyl) Phthalate
References - Continued
 [117] Singh, A. R.,  et al.  Mutagenic and Antifertility Sensi-
      tivities of Mice to Phthalic-Acid Esters.  J. Anim. Sci.,
      38(1):216, 1974.
 [118] Taylor, B. F., and E. F. Corcoran.  Biodegradation of
      Phthalic Acids and Esters.  Contract ES-00994-02, National
      Institute of Environmental ^ealth Sciences, 1975.

 [119] Autain, J.  Toxicity and Health Threats of Phthalate Esters,
      Review of the Literature.  Environ. Health Perspec., 4:3-26,
      1973.

 [120] Yagi, Y., et al.  Teratogenicity and Mutagenicity of a
      Phthalate Ester.  Teratology, 14:259-260, 1976.

 [121] Dillingham, E. 0., and J. Autain.  Teratogenicity, Mutage-
      nicity and Cellular Toxicity of Phthalate Esters.  Environ.
      Health Perspec. 3:81-89, 1973.
 [122] Landon, J. C.   Carcinogenesis Bioassay of Di(2-ethylhexyl)
      Phthalate.  National Cancer Institute contract with Tracer
      Jitco, Inc., 10/76-9/77., 1977.

 [123] Saeger, V. W., and E. S. Tucker.  Biodegradation of Phthalic
      Acid Esters in River Water and Activated Sludges.  Appl.
      Environ. Microbiol., 31(l):29-34, 1976.


                               121

-------
                       2,4-Diaminoanisole


2,4-Diaminoanisole (4-methoxy-m-phenylenediamine) was nonmuta-
genic in the L51178Y  mouse lymphoma cell test  [124] and negative
on rat skin [125]  (in combination with other chemicals) and mouse
skin [126]  (the sulfate form)  carcinogen tests.  It did not pro-
duce dominant lethal  mutations in rats [127].

It has been shown to  be mutagenic in S.  typhimurium [128-130],
usually with S-9 activation.   It also induced sex-linked reces-
sive lethal mutations in Drosophila melanogaster [131]  (sulfate
form) with peak activity in the active germ cells  (spermatids
and spermatocytes).   Preliminary results from an NCI study indi-
cate that rats and mice fed this chemical (0.12% to 0.24%) had
an excess of site-specific (thyroid and skin) malignant tumors
[133].  Also,  two epidemiologic studies suggest excess cancer
among cosmetologists  [132].  Diaminoanisole is on the NIOSH
Safety Alert list for its carcinogenic potential [133] and will
be considered a probable carcinogen for this project.

Production and Persistence

NIOSH is unaware of any current domestic production but reports
that on the order of  25,000 pounds per year are imported  [133].
[124]  Palmer,  K.  A.,  et  al.   The Mutagenic Assay of Some Hair
      Dye  Components  Using  the Thymidine Kinane Locus of L51178Y
      Mouse  Lymphoma  Cells  (Meeting Abstract).   Toxicol. Appl.
      Pharmacol.,  37(1):108,  1976.

[125]  Kinkel,  H.  J.,  and S.  Holzmann.   Study of Long-Term Percu-
      taneous  Toxicity and  Carcinogenicity of Hair Dyes (Oxidiz-
      ing  Dyes)  in Rats. Food Cosmet.  Toxicol., 11(4):641-648,
      1973.

[126]  Burnett,  C.,  et al.   Long-Term Toxicity Studies on Oxida-
      tion Hair Dyes.  Food Cosmet. Toxicol., 13 (3) :353-357 ,
      1975.

[127]  Burnett,  C.,  et al.   Dominant Lethal Mutagenicity Study
      on Hair  Dyes.   J-  Toxicol. Environ.  Health,  2 (3):657-662,
      1977.

[128]  Dybing,  E.,  and S. S.  Thorgeirsson.   Metabolic Activation
      of 2,3-Diaminoanisole,  a Hair-Dye Component.  Biochem.
      Pharmacol.,  26 (8):729-734, 1977.

[129]  Dybing,  E.,  and T. Aune.  Hexachlorobenzene Induction of
      2,4-Diaminanisole  Mutagenicity in Vitro.   Acta Pharmacol.
      Toxicol.,  40 (5) :575-583, 1977 (24 references).
                               122

-------
2, 4-Diaminoanisole
References - Continued
[130]  Ames.  B.  N.,  et al.   Hair Dyes are Mutagenic; Identifica-
      tion  of a Variety of Mutagenic Ingredients.  Proc.  Natl.
      Acad.  Sci.  (USA)  72 (6) :2423-2427,  1975.

[131]  Blijleven, W.  G.   Mutagenicity of  Four Hair Dyes in Drosph-
      ila Melanogaster. Mutat. Res., 48 (2) :181-185,  1977.

[132]  Health Hazards;  2,4-Diaminoanisole.   Occupational Safety &
      Health Reporter,  7(35):1331,  1978.

[133]  2,4-Diaminoanisole (4-Methoxy-m-phenylenediamine) in Hair
      and Fur Dyes.   Current  Intelligence Bulletin 19, January 13,
      1978.
                               123

-------
                             Diazinon

Diazinon has been reported to be slightly teratogenic in rats
when given on the llth day of gestation  [134].  An increase in
chromatid breaks has been noted in the lymphocytes of humans after
ingestion of phosphate insecticides including diazinon  [135] and
in cultivated human lymphocytes [136].

On the other hand, diazinon has been found to be nonmutagenic in
S.  typhimurium mutation tests [137].

Diazinon also does not cause mutations in the 5-MT E. coli test
[138], the WP2 TRY - to prototrophy E. coli test [139], two other
E.  coli tests [18], or a 5.  cerevisiae mitotic gene conversion
test  [18].

The majority of the information indicates that diazinon is prob-
ably not a carcinogen.
[134] Kimbrough, R. D., and T. B. Gaines.  Effect of Organic Phos-
      phorous Compounds and Alkylating Agents on the Rat Fetus.
      Arch. Environ. Health, 16:805-808, 1968.

[135] Trinh-Van-Bao, et al.  Chromosome Aberrations in Patients
      Suffering Acute Organic Phosphate Insecticide Intoxication.
      Humangenetik, 24:33-57, 1974.

[136] Tzoneva-Maneva, M. T., et al.  Influence of Diazinon and
      Lindane on the Mitotic Activity and the Caryotype of Human
      Lymphocytes, Cultivated in Vitro.  Bibl. Haematol.  (Base 1),
      38 (1) :344-347, 1971.

[137] Marshall, T. C., et al.  Screening of Pesticides for Muta-
      genic Potential Using Salmonella Typhimurium Mutants.
      J. Agric. Food Chem., 24:560-563, 1976.

[138] Mohn, G.  5-Methyltryptophan Resistance Mutations in Escher-
      ichia Coli K-12.  Mutat. Res., 20(1):7-15, 1973.

[139] Ashwood-Smith, M. J., et al.  Mutagenicity of Dichlorvos.
      Nature, 240:418-419, 1972.


                               124

-------
                        o-Dichlorobenzene


A negative animal study of o-dichlorobenzene  (CAS No. 95-50-1)
has been conducted [5], but it was a short-term  (<6 months)
study which would not be expected to show carcinogenicity.  A
few positive case studies have been reported, but with insuffi-
cient supporting evidence to show cause and effect  [140].  A few
in vitro tests have been conducted [141-143].  In Aspergillus
nidulans,  200 mg/ml for 60 minutes causes an  increase in rever-
sion to methionine prototrophy from 3 x 106 to 5 x  106 reversions
[32].  It was negative in a S.  typhimurium spot test at 1-5 yl
in eigth strains[32].  Because of the limited positive test data
on systems which have not been extensively evaluated, o-dichloro-
benzene will be considered a probable noncarcinogen  (with some
significant positive data) for this project.
 [140] IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 7, 1974.  pp. 231-244.
 [141] Guerin, M.,  et al.  Inhibitory Action of Chemical Carcino-
      gens on Mitosis of Rat Lung Cell Cultures; 2.  Comparative
      Study of Carcinogenic and Noncarcinogenic Substances.
      C. R. Soc. Biol., 165:2255-2258, 1971.

 [142] Prasad, I.  Mutagenic Effects of the Herbicide 3',4'-Di-
      chloro-propionanilide and Its Degradation Products.  Can.
      J. Microbiol., 16:369-372, 1970.

 [143] Prasad, I.,  and D. Pramer.  Mutagenic Activity of Some
      Chloroanilines and Chlorobenzenes.  Genetics, 60:212-213,
      1968.
                                125

-------
                        p-Dichlorobenzene


Many negative animal studies of p-dichlorobenzene  (CAS No.
106-46-7)  have been conducted  [5], but all of them have been
short-term (<9 months)  studies which would not be expected to
show carcinogenicity.   A few positive case studies have been
reported but with insufficient supporting evidence to show cause
and effect [140].  A few in vitro tests have been conducted  [141-
143].  It is reported that p-dichlorobenzene is a mutagen to
higher plants and causes chromosomal breaks [56],  In Aspergillus
nidulans ,  200 mg/ml for 60 minutes causes an increase in reversion
to methionine prototrophy from 3 x 106 to 11 x 10s reversions
[32].  Because of the limited positive test data on systems which
have not been extensively evaluated, p-dichlorobenzene will be
considered a probable noncarcinogen with some significant positive
data) for this project.
                               126

-------
                        Dichlorobenzidine
3,3'-Dichlorobenzidine (CAS No. 91-94-1) has been found to be
carcinogenic in the rat following oral and subcutaneous adminis-
tration and in the hamster after oral administration  [144, 145].
Many other positive responses are noted in TOXLINE and CANCERLINE,
and it is considered a probable carcinogen for this project.

Production and Persistence

It is estimated that 2.1 x 106 kg is produced per year with
4.5 x 103 kg per year released [60].  Other estimates of produc-
tion are 1.6 x 106 kg in 1971  [144]  and 2.1 x 106 kg per year [6].
Dichlorobenzidine is somewhat reactive towards R02  (tig = 40 days)
and very reactive towards HO and 03  (tj^ = 1 day)  [60] .  Its melt-
ing point is 133°C  [144].
 [144]  IARC Monographs:  Evaluation  of  the  Carcinogenic  Risk  of
       Chemicals to Man, Volume  4, 1974.  pp.  49-55.

 [145]  Stula, E. F., et al.  Experimental Neoplasia  in Rats from
       Oral Administration of  3,3-Dichlorobenzidine,  4,4'-Methyl-
       ene bis(2-chloroaniline),  and 4,4'-Methylene  bis(2-methylani
       line).  Toxicol. Appl.  Pharmacol., 31 (1) :159-176,  1975.


                                127

-------
                         Dichlorobutene
1,4-Dichlorobutene-2 is a mutagen of S.  typhimurium with micro-
somes enhancing the effect [146].  3,4-Dichlorobutene-l is also
a mutagen in that system with or without nicotinamide adenine
dinucleotide phosphate (NADP),  giving 490 reverts/ymole with NADP
and 345 reverts/ymole without NADP [146].  Trans-I,4-dichloro-
butene-2 has been found to be a weak carcinogen to ICR/HA Swiss
mice when given by subcutaneous injection or by intraperitoneal
injection but not by skin application [147].  It was found not
to be a tumor initiator in a two-stage test  [147].  Because of
the carcinogenic and mutagenic data, it has been placed on the
probable carcinogen list for this project.

Production and Persistence

It is estimated that 8.7 x 105 kg is emitted per year in the manu-
facture of polychloroprene [1].  1,4-Dichlorobutene has a boiling
point of 158°C  [33] .
 ;i46] Bartsch, EL, et al.  Alkylating and Mutagenic Metabolites
      of Halogenated Olefins Produced by Human and Animal Tissues.
      Proc, Am. Assoc. Cancer Res., 17:17, 1976.

 ;i47] Van Duuren, B. L., et al.  Carcinogenic Activity of Di- and
      Tri-functional a-Chloro Ethers and of 1,4-Dichlorobutene-2
      in ICR/HA Swiss Mice.  Cancer Res., 35:2553-2557,  1975.
                                128

-------
                     Dichlorodifluoromethane
Dichlorodifluoromethane (Freon-12) has been shown to be nonmuta-
genic in 5.  typhimurium tests [148] but may cause some (mutagenic?)
changes in conidia formation in Neurospora cvassa [149].  More
information is needed on the mutagenic and carcinogenic potential
of Freons.  No other information could be found on CANCERLINE or
TOXLINE.  At the present time, it appears as if Freons are non-
carcinogens .
 [148] Andrews, A. W., et al.  The Identification of Endogeneous
      and Exogeneous Mutagenic Compounds.  4th Carcinogenesis
      Bioassay Program, Orlando, Florida, February 1976.

 [149] Stevens, S., et al.  Phenotypic and Genetic Effects in
      Neurospora Crassa Produced by Selected Gases and Gases
      Mixed with Oxygen.  Develop. Ind. Microbiol., 12:346-353,
      1971.
                                129

-------
                       1,1-Dichloroethane


The primary reference [150]  cited for 1,1-dichloroethane  (CAS No.
75-34-3)  in the NIOSH Suspected Carcinogen list shows very minor
teratogenic effects even at the highest concentration used
(6,000 ppm) .   Although there are many references to 1,2-dichloro-
ethane, TOXLINE and CANCERLINE provided no significant references
on the mutagenicity or carcinogenicity of 1,1-dichloroethane.
A recent report from the National Cancer Institute [151] disclosed
findings indicative of a possible carcinogenic potential for this
compound but could supply no conclusive evidence.   Investigators
found dose-related marginal increases in mammary adenocarcinomas
and in hemangiosarcomas among female rats and a statistically
significant increase in the incidence of endometrial stromal
polyps among dosed female mice.  For this project 1,1-dichloro-
ethane will be classified as a possible carcinogen.

Production and Persistence

It is estimated that 2.6 x 106 kg of dichloroethane is emitted
per year from stationary sources [1].  Half of the 1,1-dichloro-
ethane will evaporate from a 1-ppm water solution at 25°C in
22 minutes [33].  It has a boiling point of 57.3°C and a vapor
pressure of 180 mm at 20°C [33].
[150]  Schwetz, B. A., et al.  Embryo- and Fetotoxicity of Inhaled
      Carbon Tetrachloride,  1,1-Dichloroethanef and Methyl Ethyl
      Ketone in Rats.  Toxicol.  Appl. Pharmacol., 28:452-464,
      1974.

[151]  National Cancer Institute Draft Summaries of Bioassay Re-
      ports, 1,1-Dichloroethane.  Chem. Reg. Rep., 1(45):1597-
      1598,  1978.
                               130

-------
                     Dichloronaphthoquinone


Dichloronaphthoquinone (Dichlone) did not cause point mutation in
a microbial test system [152].   It has, however, been found to
cause reticulum cell sarcomas  (Type A) in 9/64 mice when injected
subcutaneously in B6C3F1 or B6AKF1 strains of mice compared to
14/613 reticulum cell sarcomas for the subcutaneous controls  [69].
This was significant at a 0.01 confidence level.  Because of the
limited number of mice involved, and the lack of other references
on CANCERLINE and TOXLINE, dichloronaphthoquinone will be consid-
ered a possible carcinogen for this project.

Production and Persistence

It is estimated that 900 kg/year are emitted from stationary
sources  [1].  Dichloronaphthoquinone has a melting point of 193°C
and a 7.84 vapor density  [33].
 ;i52] Anderson, K. J., et al.  Evaluation of Herbicides  for  Possi
      ble Mutagenic Properties.  J. Agr. Food Chem.,  20:649-656,
      1972.
                                131

-------
                         Dichlorophenol


Nothing was found in CANCERLINE to indicate that dichlorophenol
is a carcinogen or a mutagen.   A 1959 reference [153] cited in
the NIOSH Suspected Carcinogen list shows that 2,4-dichlorophenol
may be a promoter or cocarcinogen when applied to the skin of
mice in combination with benzene and dimethylbenzanthracene.
Other than this reference,  dichlorophenol is not listed in Refer-
ence 5.  Because of the lack of data, dichlorophenol has been
placed on the probable noncarcinogen list as a possible promoter.
1153]  Boutwell,  R.  K.,  and  D.  K.  Bosch.   The Tumor-Promoting
      Action of  Phenol  and  Related Compounds for Mouse Skin.
      Cancer Res.,  19:413-424,  1959.
                                132

-------
                         Dichloropropene


1,3-Dichloropropene at 1 ppm for 6 months has been shown to have
no  adverse effects [154].  Both cis and trans isomers are muta-
genic to TA1535 and TA100 S.  typhimurium strains without activa-
tion [31,  155, 156].   It will be considered a possible carcinogen
for this project.

Production and Persistence

It  is estimated that 6 x 107 pounds of a dichloropropane/
dichloropropene mixture is manufactured a year  [56].  Assuming
50% dichloropropene,  3 x 107 pounds is released a year.  It is
said to react with OH and 03 with a t^ = 3 days, and to have a
tjg  = 7 days in water [56] .  It has a boiling point of 104°C and
50% of a 1-ppm water solution will evaporate in 31 minutes  [33].
 [154] Torkelson, T. R., and F. Oyen.  The Toxicity of 1,3-Dichlo-
      ropropene as Determined by Repeated Exposure of Laboratory
      Animals.  Am. Indust. Hyg. Assoc. J.,  38(5):217,  1977.

 [155] DeLorenzo, F., et al.  Mutagenicity of Pesticides Contain-
      ing 1,3-Dichloropropene.  Cancer Res., 37 (6):1915-1917,
      1977.
 [156] Neudecher, T., et al.  In Vitro Mutagenicity of the Soil
      Nematicide 1,3-Dichloropropene.  Experientia,  33(8):1084-
      1085, 1977.


                               133

-------
                     Dichloropropionic Acid
Dichloropropionic acid (Dalapon)  is a herbicide which has been
found nonmutagenic in a S.  typhimurium test [152].  No other
significant data have been found, so it has been placed on the
probable noncarcinogen list.
                               134

-------
          Dichlorovinyl Dimethyl Phosphate  (Dichlorvos)


Dichlorovinyl dimethyl phosphate (DDP) has been shown to be
mutagenic in many different short-term tests  [18], including S.
typhimurium tests [157], but has been shown to be noncarcinogenic
by oral and inhalation studies in rats and mice [158].  Because
of the mutagen studies, DDP is to be listed on the possible car-
cinogen list for this project.

Production and Persistence

It is estimated that 200 kg/year is emitted from stationary
sources  [1].  DDP has a boiling point of 120°C at 14 mm [33].
 [157] Shirasu, Y., et al.  Mutagenicity  Screening of Pesticides
      in the Microbial System.  Mutat. Res.,  40:19-30,  1976.

 [158] Bioassay of Dichlorvos  for Possible Carcinogenicity,  CAS
      No. 62-73-7.  National  Technical Information  Service  No.
      PB 270 937, 1977.
                                135

-------
                        Dimethylacetamide


Dimethylacetamide was negative in a mitotic index test for epi-
dermal hyperplasia [159].   It is cited in the NIOSH Registry of
Toxic Effects of Chemical  Substances as being teratogenic to rats
after intraperitoneal (I.P-) injection.  One reference was found
in the Survey of Chemical  Substances Which Have Been Tested for
Carcinogenic Activity (1968-1969) in which rats were given the
chemical intergastrically  at 0.1 to 30 mg/d for 260 doses [160].
The tumors found do not appear to be related to dose.  No other
references could be found  in CANCERLINE or TOXLINE which would
suggest that dimethylacetamide is a mutagen or a carcinogen, so it
will be classified as a probable noncarcinogen for this project.
 [159] Rieger, M. M.  Cosmetic Science:  1975 Literature Survey.
      Cosmet. Perfum.,  91(4):25-36, 1976.

 [160] Hadidian, Z., et al.   J. Nat. Cancer Inst., 41 (4):985-1036,
      1968.
                               136

-------
                          Dimethylamine


Dimethylamine (methanamine, N-methyl) has been reported to com-
bine with nitrates or nitrites both in vitro and in vivo  (by
saliva or intestine flora) to form the carcinogen called dimethyl-
nitrosamine or nitrosodimethylamine  (more than 20 references in
TOXLINE.   Dimethylamine may also combine with ozone and nitrogen
tetroxide in the atmosphere [161].  In TOXLINE and CANCERLINE
there are 74 and 16 references, respectively, which deal with
mutagenic or carcinogenic aspects of dimethylamine.  These refer-
ences, along with those in Chemical Abstracts, appear to indicate
that although dimethylamine is a potent cocarcinogen, it is not
by itself carcinogenic.  For this project, it will be considered
a noncarcinogen but will be considered when cofactors are
evaluated.
 :i61] Dushutin, K. K., and E. D. Sopach.  The Role of the Reaction
      of Dimethylamine with Nitrogen Tetroxide and Ozone in Atmos-
      pheric Pollution.  Gig. Sanit., 7:14-18, 1976.
                                 137

-------
                        Dimethylhydrazine


1,1-Dimethylhydrazine (CAS No. 57-14-7) has been found to be
carcinogenic in mice after oral administration  [162].  It also
causes tumors of the colon in rats (but not swine, dogs, or
guinea pigs - perhaps because of toxicity) fed  30 mg/kg dimethyl-
hydrazine [163].  Many other positive references are found in
TOXLINE and CANCERLINE,  and it is considered a  probable carcino-
gen for this project.

Production and Persistence

Production is estimated at <5 x 105 kg in 1973  [6, 8, 162], with
a 0.01 fraction of dispersion [6].  Since it is polar, nonvolatile,
and soluble in water, there would not be a significant transfer
to the atmosphere [8].  It reacts with oxidizing materials in the
atmosphere  [6] and has an expected half-life of 2.1 hours by re-
action with the HO radical [8].  Dimethylhydrazine has a boiling
point of 63.3°C and a vapor pressure of 157 mm  at 25°C [6].
[162]  IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 4, 1974.  pp. 137-143.

[163]  Wilson, R. B.  Species Variation in Response to Dimethyl-
      hydrazine.  Toxicol. Appl. Pharmacol., 38 (3) :647-650, 1976
                                138

-------
                         Dinitrotoluene
2,4-Dinitrotoluene has been found by the National Cancer Institute
to be noncarcinogenic to mice but carcinogenic to rats [164].  It
has been placed on the probable carcinogen list for this project.

Production and Persistence

It is estimated that 400 kg dinitrotoluene is emitted per year
from stationary sources [I].   It has a boiling point of 300°C
[33].
 [164] National Cancer Institute Draft Summaries of Bioassay
      Reports, 2,4-Dinitrotoluene.  Chem. Reg. Rep., 1(45):1598,
      1978.
                               139

-------
                             Dioxane


1,4-Dioxane (CAS No.  123-91-1)  has been shown to be carcinogenic
to rats [165,  166]  and guinea pigs [167] by oral administration.
It produced malignant tumors of the nasal cavity and liver in rats
and tumors of the liver and gall bladder in guinea pigs.  It was
also active as a promoter in a two-stage skin carcinogenesis
study in mice but produced no carcinogenic effect in one inhala-
tion study in rats [168].  For this project, it is considered a
probable carcinogen.

Production and Persistence

The 1972 production has been estimated to be 6.3 x 106 kg [6, 44,
167] and the 1973 production to be 7.4 x 106 kg [167], with most
of this being released to the environment [44].  In the atmos-
phere it reacts with the HO radical with a half-life of 9.6 hours
[6, 44].  It has a boiling point of 101°C and a vapor pressure of
30 mm at 20°C and 37-39 mm at 25°C [6, 33, 167].
 [165] Kociba, R. J., et al.  1,4-Dioxane:  Correlation of the
      Results of Chronic Ingestion and Inhalation Studies with
      its Dose-Dependent Fate in Rats.  Aerosp. Med. Res. Lab.
      (Tech. Rep.) AMRL-TR-125, 1975.  pp. 345-354.

 [166] Argus, M. F., et al.  Dose-Response and Ultrastructural
      Alternatives in Dioxane Carcinogenesis.  Eur. J. Cancer,
      9(4):237-243, 1973.

 [167] IARC Monographs:  Evlauation of the Carcinogenic Risk of
      Chemicals to Man, Volume 11, 1976.  pp. 247-256.

 [168] Torkelson, T. R., et al.  1,4-Dioxane.  II.   2-Year Inhala-
      tion Study in Rats.  Toxicol. Appl. Pharmacol., 30(2):
      287-298, 1974.
                                140

-------
                         Diphenyl Oxide


No positive or negative data could be found for diphenyl oxide
(phenyl ether, CAS No. 101-84-8) on TOXLINE, CANCERLINE, or in
the Survey of Compounds Which Have Been Tested for Carcinogenic
Activity (Volumes 1-7).  It is, therefore, listed as a probable
noncarcinogen for this project.
                                141

-------
                    Disodium Methanearsonate
Disodium methanearsonate has been cited as being carcinogenic,
but no further data are given in this reference  [6].  It has
been found to be nonmutagenic when tested with five strains of
S.  t'^phimurium,  mitotic recombination of S.  cerevisiae, and rela-
tive toxicity assays in E.  ooli and B.  subtilis  [169].  In all
tests except the B.  subtilis, the chemical was tested using the
S-9 microsome activation.  Methanearsonates have also been tested
for mutagenesis  by other authors [152,  157].  The lack of confirm-
ing data from TOXLINE or CANCERLINE and all indications other than
the first reference demonstrate that this chemical is probably a
noncarcinogen.
[169]  Simmon,  V.  F.,  et al.   In Vitro Mutagenic Studies of Twenty
      Pesticides.   Toxicol.  Appl.  Pharmacol.,  37(1):109, 1976.
                               142

-------
                             Dursban
Dursban has been shown to be more toxic to the repair deficient
strains of B.  subtilis and E. ^oli than in repair proficient
strains of these organisms.  It was not, however, found to be a
mutagen on S.  typhimurium assays or on the mitotic recombination
of S.  cerevisiae [169].   It is considered a noncarcinogen for
this project.
                               143

-------
                           Endosulfan
Endosulfan has been found to marginally increase  (P = 0.05)
the total number of tumors and the pulmonary adenomas in mice
given the compound orally [69].  Endosulfan has been found to
be nonmutagenic in three different E.  coli mutagen tests [18].
In a National Cancer Institute study [170], endosulfan was found
to be noncarcinogenic to both mice and rats.  Because of the
limited amount of positive carcinogenic data and the many negative
studies,  endosulfan has been placed on the probable noncarcinogen
list.
.170]  National Cancer Institute Draft Summaries of Bioassay
      Reports.  Chem. Reg.  Rep.,  1 (45) :1608-1609,  1978.
                               144

-------
                             Endrin
Endrin (CAS No. 72-20-9) has been reported to cause chromosome
breakage in cells [171].  Endrin was nonmutagenic by a S. typhi-
murium test using mouse liver microsomes  [172] and has tested
negative on several E.  coli tests [18].  Rat feeding studies  (up
to 100 ppm) showed no increase in tumor incidence  [173].  Endrin
will be considered a probable noncarcinogen for this project.
 [171] Grant, W. F.  Cytological Effects of Environmental Mutagens-
      Pesticides.  Mutat. Res., 21 (4):221-222,  1973.

 [172] Van Dijck, P-, and H. Van de Voorde.  Mutagenicity Versus
      Carcinogenicity of Organochloride Insecticides.  Meded.
      Fac. Landbouwwet., Rijksuniv-  Gent, 41(2, part  2):1491-
      1498, 1976.

 [173] IARC Monographs:  Evaluation of  the Carcinogenic Risk of
      Chemicals to Man, Volume 5, 1974.  pp.  157-171.
                               145

-------
                         Epichlorohydrin


Epichlorohydrin (chloromethyl oxirane, l-chloro-2,3-epoxy-propane;
CAS No.  106-89-8)  has been reported to be carcinogenic in mice by
subcutaneous injection and active as an initiator in a two-stage
skin carcinogensis study in mice [174].   Epichlorohydrin is also
a mutagen causing chromosome aberrations, mutating S. typhimurium
in a host mediated assay and inducing reversions to prototrophy
in S.  typhimurium, E.  ooli, and Neurospora cvassa [32].  It will
be considered a probable carcinogen for this project.

Production and Persistence

It is estimated that 2.2 x 10s kg is emitted per year  [1].   Pro-
duction in 1973 was estimated [8, 32, 174] to be 1.6 x 10s kg,
1.5 x 10s kg and 8.2 x 107 kg with a more recent estimate [6]  of
2.2 x 108 kg.  The production is expected to grow 4-5% a year
[32].   In the atmosphere epoxides have a half-life of 3 to 11
hours [8].  Epichlorohydrin has a boiling point of 117°C and a
vapor pressure of 12 mm at 20°C  [33].
[174]  IARC Monographs:   Evaluation of the Carcinogenic Risk of
      Chemicals to Man,  Volume 11, 1976.  pp. 131-139.


                               146

-------
                              Eptam


Eptam (ethyl di-n-propylthiocarbamate, CAS No. 759-94-4) was
negative in a bone marrow chromosomal aberration test when fed
to rats at 1/5 LD50 (LD50 = 1,630 mg/kg)  [175].  Eptam may have
had an effect on Vicia faba [176].  It is cited as belonging to
the C4 classification of pesticides [88]  (negative, but in only
one species of animal) but also referenced as being a neoplastic
agent [6].  Neither of these primary references could be found
on CANCERLINE, TOXLINE, MEDLINE, or in the entire collection of
Reference 5.  For this project it will be classified as a noncar-
cinogen.
 [175] Kurinnyi, A. I.  Mutagenic Activity of Some Pesticides
      Derivatives of Urea, Carbamic, and Thiocarbamic Acids.
      Tsitol. Genet., 11 (4):357-359, 1977.

 [176] Hakeek, H., and A. Shehab.  Cytological Effects of Eptam
      and Cotoran on Vicia Faba.  Egypt. J. Hot., 16 (1-3):303-
      311, 1974.


                                 147

-------
                              Ethanol
Much has been written about the mutagenicity and carcinogenicity
of ethanol [177]  (87 references in TOXLINE) for both positive
[178] and negative  [179]  results.  It has been tested extensively
in animal systems [5].   In general it is considered a noncarcin-
ogen and nonmutagen and has been removed from the lastest NIOSH
Suspected Carcinogens List.  It will be considered a probable
noncarcinogen for this project.
 [177] Rydberg, U., and S. Skerfuing.  The Toxicity of Ethanol:
      A Tentative Risk Evaluation.  Adv- Exp. Med. Biol., 85B:
      403-419, 1977 (57 references).

 [178] Braun, R.,  and J. Schoeneick.  Influences of Ethanol and
      Carbon Tetrachloride on the Mutagenic Effectivity of Cyclo-
      phosphamide in the Host-Mediated Assay with Salmonella
      Typhimurium.  Mutat. Res., 31 (3) :191-194, 1975.

 [179] Charbey, R. C.,  et al.  Evaluation of the Effect of Ethanol
      on the Frequency of Micronuclei in the Bone Marrow of Swiss
      Mice.  Mutat. Res., 43 (3) :441-444, 1977.


                                148

-------
                          Ethylbenzene


No data have been found to indicate that ethylbenzene is a muta-
gen or a carcinogen.  A review of its use as a fragrance is
noted [180] .  Ethylbenzene has been found noncarcinogenic to
rats, guinea pigs, rabits and monkeys by inhalation and to rats
orally [7].  It is negative on the viral enhancement of hamster
cell transformation  (personal communication from B. C. Casto on
9 February 1978).  It is therefore classified as a noncarcinogen
for this project.
 [180] Opdyke, D. L.  Monographs on Fragrance  Raw Materials  Ethyl
      benzene.  Food Cosmet.  Toxicol.,  13(Suppl.):803-804,  1975.
                               149

-------
                            Ethylene
No data were found to indicate that ethylene is a mutagen or a
carcinogen.   It is also a normal metabolite of the human body.
It is therefore classified as a probable noncarcinogen for this
project.
                              150

-------
                       Ethylene Dibromide


Ethylene dibromide  (1,2-dibromoethane, ethylene bromide; CAS No.
106-93-4) has been found to produce squamous-cell carcinomas of
the forestomach in mice and rats after its oral administration
[181].  It has also been reported to be mutagenic in S. typhi-
murim, E. ooli,  Neurospora crassa, S. cevevisiae. Tradescantia.,
Serratia. maroesaens , and Drosophi-la melanogaster test  systems
[32, 75, 182].  Ethylene dibromide will be considered  a probable
carcinogen for this project.

Production and Persistence

It is estimated that 8.9 x 105 kg of ethylene dibromide is
emitted per year from stationary sources  [1].  Another reference
cites a production of 1.43 x  108 kg with  1.38 x 10s kg released
[7],  Other references cite production of 1.5 x 10s kg  (1974)
[8, 181],  1.4 x 108 kg  [6],  and 1.5 x 108 kg, 1.2 x 108 kg for
1974 and 1975 [32].  The use  of ethylene  dibromide in  gasoline
is predicted to drop by 10% a year through 1980, while its use
as a fumigant may be terminated by EPA action in light of the
above animal studies  [32].  Its air pollution potential has been
assessed  [182].  Atmospheric  oxidation of alkyl halides is re-
ported to have a half-life of less than 20 hours, while the half-
life of HO radical  attack is  234 days  [8].   Ethylene dibromide
has a boiling point of 131.6°C and a vapor pressure of 11 mm at
25°C  [181].
 [181] IARC Monographs:   Evaluation of the  Carcinogenic Risk of
      Chemicals to Man,  Volume  15,  1977.   pp.  195-209.

 [182] Johns, R.  Air  Pollution  Assessment  of Ethylene Dibromide.
      National Technical Information Service No.  PB 256 736, 1976
                                151

-------
                       Ethylene Dichloride


Ethylene dichloride (1,2-dichloroethane, ethylene chloride; CAS
:;o.  107-06-2)  has been found in preliminary results to be carci-
nogenic when fed to male and female rats by the National Cancer
Institute [183].  Rats fed ethylene dichloride had a significant
excess of site-specific  malignant and nonmalignant tumors.  In
other studies it has been negative by inhalation in rats, guinea
pigs and monkeys but mutagenic to fruit flies  [184].  Because of
the positive animal studies, it is included on the probable car-
cinogen list for this project.

Production and Persistence

It is estimated that 6.7 x 107 kg ethylene dichloride is
emitted per year from stationary sources [1].  Other references
cite a production of 3.9 x 109 kg produced with 2.1 x 10s kg
released [7],  4.2 x 109  kg  (1973) [6] produced, and production
of 4.2 x 109 kg, 3.6 x 109 kg, and 3.6 x 109 kg in 1974, 1975,
and 1976 [32].  An air pollution assessment of ethylene dichlo-
ride has been made  [184].  Ethylene dichloride reacts slowly
with peroxides with a half-life of 1,000 days and is resistant
to photochemical degradation  [184].   The HO reaction half-life
has been estimated to be 234 hours [8].  It has a boiling point
of 83.5°C and a vapor pressure of 61 mm at 20°C [33].
[183] New Findings on Two Carcinogens Reported to Subcommittee by
      NIOSH.  Occupational Safety & Health Reporter, 7(35):1331,
      1978.

[184] Johns, R.  Air Pollution Assessment of Ethylene Dichloride.
      National Technical Information Service No. PB 256 733, 1976
                               152

-------
                         Ethylene Glycol


Although ethylene glycol  (1,2-ethanediol) has been reported to
give neoplastic effects at 4 g/kg on mouse skin  [6], no other
confirming reports of carcinogenicity or mutagenicity have been
found.  Many reports indicate that ethylene glycol is noncarci-
nogenic in different species by various routes of administration.
These include 18 tests reported in 8 articles before 1950 on
rats, mice, and rabbits in food, drinking water, intravenously,
subcutaneously, intermuscularly, and via inhalation - all with
negative results  [26].

More recently, tests have been negative for ethylene glycol  [185]
including subcutaneous rat tests  [186], subcutaneous newborn mice
tests  [187], and inhalation tests using rat, guinea pig, rabbit,
dog, and monkey  [188].  It is also negative in the Salmonella
test for mutagens  [32, 52].  All in all, ethylene glycol will be
considered a noncarcinogen for this project.
 [185] Homburger, F.  Carcinogenicity of  Several Compounds.
      National Technical  Information Service No. PB  183  027,
      1968.  26 pp.
 [186] Mason, M. M.  Toxicology and Carcinogenesis of Various
      Chemicals Used in the Preparation  of Vaccines.  National
      Technical Information Service No.  PB 195  185,  1969.   55 pp.

 [187] Derse, P. H.  Injection of Newborn Mice with Seven Chemical
      Adjuvants to Help Determine Their  Safety-  National  Tech-
      nical Information Service No. PB 195 153, 1969.   135 pp.

 [188] Coon, R., et al.  Animal Inhalation Studies on Ammonia,
      Ethylene Glycol, Formaldehyde, Dimethylamine,  and Ethanol.
      Toxicol. Appl. Pharmacol., 16 (3) :645-646, 1970.


                                153

-------
                         Ethylene Oxide


Ethylene oxide (oxirane, 1,2-epoxyethane; CAS No. 75-21-8) has
been found negative on skin-painted mice and subcutaneously  in-
jected rats [189].   Short-term inhalation tests  (6 months) on
dogs, mice, rats, rabbits, guinea pigs, and monkeys were nega-
tive [189].  An excess of tumors was found in mice exposed to
ethylene oxide-treated ground-corncob bedding as an experiment
not designed to test for carcinogenicity of ethylene oxide  [189].
Ethylene oxide is a mutagen in S. typhimurium., Neurospora crassa
and Drosophila melanogaster tests [32, 189].  It will be consid-
ered a possible carcinogen for this project based on the in  vitro
mutagenicity data.

Production and Persistence

It is estimated that 4.5 x 106 kg ethylene oxide is emitted  per
year from stationary sources [1].  Other estimates of production
include  1.8 x 109  kg produced with 4.5 x 107 kg released [44],
1.8 x 109 kg produced [6], 1.8 x 109 kg produced in 1974 [8],
1.9 x 109 kg produced in 1975 [189], and 1.8 x 109 kg and
2.0 x 109 kg produced in 1974 and 1975 [32].  Its primary use
as an intermediate  is expected to grow at 4.7-5.2% per year
until 1980 [32].   Dispersed in the atmosphere, epoxides would
be oxidized by HO radicals with a 3- to 11-hour half-life [8].
Its reaction with HO radicals has also been estimated to give
half-lives of 1.6 days [44]  and 23 hours [8].  It has a boiling
point of 11°C and a vapor pressure of 1,095 mm at 20°C  [33].
 [189] IARC Monographs:  Evaluation of the Carcinogenic  Risk  of
      Chemicals to Man, Volume 11, 1976.  pp.  157-167.
                                154

-------
                          Ethylenimine


Ethylenimine (Aziridine, CAS No. 151-56-4) is well documented
as being a potent mutagen, and it is used as a mutagen in many
plant studies (533 references on TOXLINE to its use as a mutagen
or carcinogen).   It has also been found to be carcinogenic in at
least two strains of mice following oral administration, produc-
ing liver-cell and pulmonary tumors  [190] .  Subcutaneous injection
of single doses in suckling mice produced increased incidence of
lung tumors in males.  Subcutaneous injection in oil produced
local tumors in rats  [190].  It is considered a probable carcin-
ogen for this project.

Production and Persistence

It is estimated that 2.7 x 104 kg is released to the environment
per year [44].   Estimates of production are 2.3 x 106 kg,
1.4 x 106 kg, 2.2 x 106 kg (1974), and 2.3 x 106 kg per year [6,
8, 32,  44].  Ethylenimine is infinitely soluble in water [6],
basic,  and polar, and could therefore be expected to be very
slow to escape from water to the atmosphere [8].  Its reaction
with HO in the atmosphere has been found to have a half-life of
1.5 days [44],  47 hours  [8],  and 56 hours [8].  It has a boiling
point of 56°C and a vapor pressure of 160 mm at 20°C [190].
 [190] IARC Monographs:  Evaluation  of  the  Carcinogenic  Risk  of
      Chemicals to Man, Volume  9, 1976.  pp.  37-46.
                               155

-------
                          Fluoranthene
Fluoranthene (CAS No.  206-44-0)  was tested for carcinogenicity
in 1935 and 1938 on mice by skin (0.3% in benzene for 501 days)
and oral (10 mg for 18 months)  routes of administration with
negative results [5].   Arcos and Argus reported in 1974 that in
1963 or 1964 others had found fluoranthene negative by subcuta-
neous tests in XVII nc/Z strain of mice [191]; fluoranthene is
generally considered noncarcinogenic  [191].   Recent tests of
mouse skin application, alone or followed by croton oil, were
negative after 15 months and 20 weeks, respectively [192].  It
has been tested on TA98, 100 and 1537 strains of S.  typhimurium
for mutagenicity [193].  It is  considered a probable noncarcino-
gen for this project.
[191  Arcos,  J.  C.,  and M.  F.  Argus.   Chemical Induction of
      Cancer,  Volume 11A.   Academic Press, New York, 1974.
      pp.  26,  237.

[192]  Hoffman,  D.,  et al.   J.  Natl. Cancer Inst., 49:1165-1175,
      1972.

[193]  Rao,  T.  K.,  et al.   Environmental Mutagenesis of Energy-
      Related  Effluents.   Genetics, 83:360, 1976.
                               156-

-------
                          Formaldehyde


Formaldehyde  (methanal, formalin, methyl aldehyde; CAS No. 50-00-0)
has been tested for carcinogenicity with negative results on many
animal species in short-term  (usually less than a year) tests  [5].
However, 1,300 mg/kg  (65 weeks) caused neoplastic effects in rats
[6], and 1 ml of 0.4% formaldehyde solution caused spindle cell
sarcomas and fibrosarcomas at the injection site of  4/10 rats
evaluated at least 649 days  [194].  Formaldehyde has been shown
to be a mutagen in Drosophila melanogaster1, E. ooli, barley, Vioia
faba, yeast, and viral transformation enhancement tests  [4, 44,
and personal communication with B. C. Casto on 9 February 1978],
but negative on the mouse dominant lethal test  [30].  For this
project formaldehyde will be considered a possible carcinogen.

Production and Persistence

It is estimated that 4.1 x 107 kg formaldehyde is emitted per
year from stationary sources with 82% of this being  from charcoal
manufacture and catalytic cracking in petroleum refining  [1].
Other estimates of production include 2.6 x 109 kg produced and
2.4 x 107 kg released  [6], 2.6 x  109 kg produced and 6.4 x 107 kg
released  [44], 2.6 x 109 kg produced  (1974)  [8], and 2.9 x 109 kg
and 2.6 x 109 kg produced in  1973 and 1975  [32].  The production
of formaldehyde is projected  to grow by 4-5% per year in the next
5 years  [32].  In solution it is  essentially nonvolatile, but  in
air it will react with HO radical with a half-life of 2.6 hours
 [8] or 1.2 hours  [44].  As a  gas  it has a boiling point of -21°C
and a vapor pressure of 1,946 mm  at 25°C  [6].  Its environmental
fate and biological and environmental effects have been studied
 [195] .
 [194] Watanabe, F., et al.  Gann,  45:451-452,  1954  (as  cited  in
      Reference 5).
 [195] Investigation of Selected  Potential  Environmental Contami-
      nants:  Formaldehyde.  National  Technical  Information
      Service No.  PB  256  839,  1976.
                               157

-------
                             Guthion
Guthion has been found to be mutagenic in that it induced chromo-
some breaks in diploid [WI-38 (female embryonic lung)] and hetero-
ploid [HEp-2 (male neoplastic larynx)] cells  [196].   Guthion also
increased mitotic recombination in S.  cerevisiae  [169].  However,
it did not prove to be a mutagen in S. typhimurium assays  [169]
or in E.  coli or B.  subtilis systems  [169] and did not induce
dominant lethal effects in mice [197].  For this project it is
considered a noncarcinogen.
[196]  Alam,  M.  T.,  and S.  S.  Kasatiya.   Cytological Effects of an
      Organic Phosphate Pesticide on Human Cells in Vitro.  Can.
      J.  Genet.  Cytol., 18(4):665-671,  1976.

[197]  Jorgenson,  T.  A., et al.   In Vivo Mutagenesis Investiga-
      tions  of  Ten  Commercial Pesticides.   Toxicol. Appl.
      Pharmacol.,  37(1):109,  1976.
                               158

-------
                            Heptachlor


The IARC monograph on heptachlor  (heptachloro-tetrahydro-
methanoindene, CAS No. 76-44-8) shows this compound to have
both positive and negative data, with more negative than
positive [198].  It is a mutagen as tested by the enhancement
of viral transformation  (personal communication with B. C. Casto
on 9 February 1978).   Recent NCI tests  [199] with rats and mice
demonstrated that heptachlor is a carcinogen for the liver in
mice under the conditions of their bioassay-  It is considered
a probable carcinogen for this project.

Production and Persistence

It is estimated that 1.1 x 104 kg heptachlor is emitted per year
from stationary sources  [1].  Estimates of production include
2.7 x 106 kg  (1971) and  2.7 x 106 kg produced [6].  It has a
melting point of 95°C and a vapor pressure of 3 x lO"" mm at 25°C
[198] .
 [198] IARC Monographs:  Evaluation  of  the  Carcinogenic  Risk  of
      Chemicals to Man, Volume  5, 1974.  pp.  173-191.

 [199] Bioassay of Heptachlor  for Possible  Carcinogenicity, CAS
      No. 76-55-8.  National  Technical Information  Service No.
      PB  271  967.
                                159

-------
                        Hexachlorobenzene
Hexachlorobenzene (benzene hexachloride, CAS No.  118-74-1)  induces
microsomal enzymes [129], is only slightly teratogenic  [200],  and
tests positive/negative  [30] and negative  [200] on the  dominant
lethal test in rats.   When fed to rats it was noncarcinogenic
[201], and by S.  typhimurium tests  (using mouse liver microsomes)
it was negative  [172].

Hexachlorobenzene was,  however, mutagenic when tested with  S.
cerevisiae at 100 ppm  [202], and when fed to 6-week-old Syrian
golden hamsters at concentrations up to 200 ppm it induced
hepatomas, hemangiomas and thyroid adenomas in a  dose response
manner [203].  It is therefore considered a possible carcinogen
for this project.

Production and Persistence

It has tJj ^2 days in the air, reacting with OH to form  penta-
chlorophenol.  Its production is estimated to be  6 x 105 kg per
year, and 1.3 x 105 kg is used in a dispersive manner as a  fungi-
cide for a total of 2.2 x 105 kg released  [7].  It has  a boiling
point of 332-326°C [33].
 [200] Khera, K. S.  Hexachlorobenzene:  Teratogenicity and Domi-
      nant Lethal Studies in Rats.  Toxicol. Appl. Pharmacol.,
      29(1):109, 1974.

 [201] Boyland, E., et al.  Kidney Tumors in Rats Following Treat-
      ment with 2-Acetylaminofluorene, Tryptophan, and 14-Sacchar-
      olactone and the Failure of Substances Which Cause
      Porphyrinuria to Induce Tumors.  In:  British Empire Cancer
      Campaign 1963 - Part 2:  Scientific Report, 1963.  pp.  58-59.

 [202] Guerzoni, M. E., et al.  Mutagenic Activity of Pesticides.
      Riv. Sci. Tecnol. Alimenti Nutr. Urn.  (Ital.), 6(3):161-165,
      1976.

 [203] Cabral, J. R. P., et al.  Carcinogenic Activity of  Hexachlo-
      robenzene in Hamsters.  Nature, 269 (5628) :510-511,  1977.
                                160

-------
                       Hexachlorobutadiene
Hexachlorobutadiene injected I.P. in mice apparently caused no
lung adenomas [204].  A study with rats on diets containing hexa-
chlorobutadiene showed no effects at 0.2 mg/kg/day or less, but
renal tubular adenomas and adenocarcinomas at 2 and 20 mg/kg/day
[205, 206].  A reproduction study also showed no effects at 0.2
but effects at 20 mg/kg/day.  At the high doses some toxicity
was also evident.  A 90-day feeding study  (0.3-30 ppm) on Japanese
quail showed little effect of this chemical  [207].  NIOSH has a
safety alert out on the basis of the above tests, and hexachloro-
butadiene is considered a possible carcinogen for this study.

production and Persistence

It is estimated that 3.6 x 106 kg is produced in the United States
with 3.3 x 106 kg being released per year  [7].  It reacts with
OH and 03 with a tj- of less than 1 day and has a low water solu-
bility  [7].  The boiling point of hexachlorobutadiene is 210°C
with a vapor pressure of 22 mm at 100°C  [33].
 [204] Test for Carcinogenicity  of  Organic Contaminants  of United
      States Drinking Waters by Pulmonary Tumor  Response in  a
      Strain of Mice.  Cancer Res.,  37(8):2717-2720,  1977.

 [205] Results of a Two-year Chronic  Toxicity  Study with Hexachlo-
      robutadiene in Rats  (Meeting Abstract).  Toxicol. Appl.
      Pharmacol., 41(1):204, 1977.
 [206] Kociba, R. J. , et  al.  Results of  a Two-Year Chronic Toxi-
      city Study with Hexachlorobutadiene in  Rats.  Am. Ind. Hyd
      Assoc. J., 38 (11) :589-602,  1977.

 [207] Reproduction Study in Japanese Quail  Fed Hexachlorobuta-
      diene for 90 days.  Toxicol. Appl. Pharmacol.,  30 (2):255-
      265, 1974.
                                161

-------
                     Hexamethylenetetramine


Hexamethylenetetramine (CAS No. 100-97-0) has been extensively
tested in both rats and mice [5].   Almost all of these tests show
that this chemical is noncarcinogenic when given either orally
(up to 5% of drinking water) or subcutaneously  (25 g/kg)  [208].
It has been tested on E.  ooli differential growth  (pol A) test
with positive results which was considered a false positive  [46].
It has also been reported to be nohmutagenic to Drosophila, posi-
tive in oral mouse dominant lethal test, negative in an intra-
peritoneal mouse dominant lethal test, and positive on a chromo-
somal abberation test in cultured lymphocytes [32].  Hexamethy-
lenetetramine will be considered a noncarcinogen (with some
positive data) for this project because of the extensive negative
animal data.
[208]  Delia Porta,  G.,  et al.   Non-Carcinogenicity of Hexamethyl-
      enetetramine  in Mice and Rats.   Food Cosmet. Toxicol.,
      6 (6) :707-715,  1968.
                                162

-------
                            Hydrazine


Hydrazine (diamine, CAS No. 302-01-2) has been shown to be car-
cinogenic in mice after oral and intraperitoneal administration
and in rats following oral administration  [209].  It was negative
in hamsters after oral administration  [209].  Hydrazine is con-
sidered a probable carcinogen for this project.

Production and Persistence

It is estimated that 3.5 x 103 kg hydrazine is emitted per year
[1].   In 1966, production of hydrzine was 7 x 106 kg per year
with more than 70% of this going toward rocket fuels  [209] .  Pro-
duction was estimated at 1.4 x 106 kg in 1971 and at 1.7 x 107 kg
in 1974  [8, 32].  The demand for hydrazine is expected to  increase
15-17%  a year until 1985  [32].  Hydrzine is polar, nonvolatile
and water soluble, suggesting that it will not transfer to the
atmosphere at significant rates  [8].  Oxidation by HO radicals
in the gas phase is reported to be rapid with a half-life of less
than 1 hour [8].  It has a boiling point of 113°C and a vapor
pressure of 16 mm at 20°C  [33].
 ,209]  IARC Monographs:   Evaluation of  the  Carcinogenic Risk of
       Chemicals  to  Man,  Volume  5,  1974.  pp.  127-136.
                                163

-------
                          Hydroquinone


Hydroquinone is listed on the NIOSH Suspected Carcinogen List,
but it is apparently there by mistake.  The 1955 reference cited
[210]  shows 20 mg of hydroquinone applied to the skin of mice
(in benzene) developed only 1 tumor out of 22 surviving mice as
compared with 1 tumor out of 22 surviving mice for the croton oil
control.  A more recent reference cites hydroquinone as a bladder
carcinogen when implanted in cholesterol pellets, producing 32%
tumors vs 12% for the cholesterol control [211].  Hydroquinone is
said to be an inhibitor of 3,4-benzopyrene carcinogenesis [212],
inactive as a promoter [213], and slightly active as a promoter
[214]  of carcinogenesis.

Hydroquinone has been reported as more toxic to repair deficient
E.  coli  (pol A~) indicating that it may induce DNA damage [32],
but negative in inducing antibiotic resistance in Miovococous
pyrogens [32].  Chromosome aberrations have been noted in several
plant systems after treatment with hydroquinone  [32].  These muta-
genic references almost place hydroquinone on the possible carcin-
ogen list,  but they involve test systems which have not been
extensively evaluated.  Hydroquinone will be considered a probable
noncarcinogen (with some significant positive data) for this
project.
 [210] Roe, F. J. C., and M. H. Salaman.  Further Studies on In-
      complete Carcinogenesis.  British J. of Cancer, 9:177-203,
      1955.

 [211] Boyland, E., et al.  Further Experiments on Implantation of
      Materials into the Urinary Bladder of Mice.  British J. of
      Cancer, 18:575-581, 1964.

 [212] Van Duuren, B. L., and B. M. Goldschmidt.  Cocarcinogenic
      and Tumor-Promoting Agents in Tobacco.  J. Natl. Cancer
      Inst., 56:1237-1242, 1976.

 [213] Hecht, S. S., et al.  Study of Tobacco Carcinogenesis; XIII:
      Tumor-Promoting Subfractions of the Weakly Acidic Fraction.
      J. Natl. Cancer Inst., 55 (6) :1329-1336, 1975.

 [214] Interaction Between Hydroquinone and Cigarette  Smoke Con-
      densate in Short-Term Skin Tests for Carcinogenicity.
      TOXLINE.
                                164

-------
                            Kelthane
Kelthane has been found nonmutagenic to E. ooli bacteria in the
WP2 TYR to prototrophy test [139].  It is considered a probable
noncarcinogen for this project.
                                165

-------
                            Malathion
Malathion has been demonstrated not to be a teratogen  [134] , and
Ames et al. consider it not to be a mutagen [52].  It has been
found to be nonmutagenic in four test systems  [18], and a study
by the National Cancer Institute found it to be  noncarcinogenic
to rats and noncarcinogenic to mice [215].  Malathion was found
nonmutagenic by a dominant lethal test in mice  [197] but was a
slight promoter in rats when given with dimethylbenz(a)anthra-
cene [216].  For this project Malathion is classed as a probable
noncarcinogen.
[215]  National Cancer Institute Draft Summaries of Bioassay
      Reports.  Chem. Reg.  Rep., 1 (45) :1602-1603,  1978.
[216]  Silinskas,  K.  C.,  and A.  B.  Okey.   Protection by DDT
      Against Mammary Tumors and Leukemia During Prolonged Feed-
      ing of 7,12-Dimethylbenz(a)anthracene to Female Rats.  J.
      Natl.  Cancer Inst.,  55 (3):653-658,  1975.
                               166

-------
                        Maleic Anhydride


Only one 1963 reference cites maleic anhydride as a carcinogen
[217].  In this paper three rats of an unspecified species were
injected 550 times with maleic anhydride.  Two of the three rats
developed fibrosarcomas at the injection site.  No other indica-
tions could be found in the literature suggesting that maleic
anhydride may be a mutagen or a carcinogen in any test systems.
In the atmosphere maleic anhydride could be expected to be con-
verted rather rapidly to maleic acid for which no evidence has
been found to suggest it has any carcinogenic or mutagenic
potential.  Since maleic anhydride has some degree of toxicity
and is a lacrimator, animal studies will probably show it to be
a noncarcinogen.
 [217] Dickens, F., and  H. E.  H.  Jones.   Further  Studies  on  the
      Carcinogenic and  Growth-Inhibitory Activity  of  Lactones and
      Related  Substances.   Brit.  J.  Cancer,  17:100-108,  1963.
                                167

-------
                      Mercaptobenzothiazole


Mercaptobenzothiazole (2-benzothiazolethiol, Captax; CAS No.
149-30-4)  was one of the 80 chemicals evaluated as having the
greatest potential for environmental effects  [7].  This report
cited a negative mice feeding study  [77] in which two groups of
36 mice of slightly different strains were given 464 mg/kg mercap-
tobenzothiazole in gelatin orally on days 7-28 and then 1,492 ppm
in their diet for 17 months with no increase in tumors found.
Seventeen months is a little on the short side for carcinogen
evaluation by present standards.

In another study [69] mercaptobenzothiazole was given orally and
subcutaneously at 100 and 215 mg/kg, respectively, to two mouse
strains (36 mice per strain).  It was found to cause a statis-
tistically significant  (0.01 level) increase in type A reticulum
cell sarcomas when given subcutaneously-  It may have been tested
for mutagenicity [218] and teratogenic activity, but the results
are unclear  [219].   Because of the limited tests thus far con-
ducted, more in vivo or in vitro data might change its classifi-
cation but it will be considered a possible carcinogen for this
project.a

Production and Persistence

The production of mercaptobenzothiazole is estimated at 2.7 x 106
kg per year with the release of 2.7 x 10^ kg per year [7],  It
is reactive towards RO  (tj^ = 8 days) , HO (t^ = 1 day) , and 03
(tjg = 9.6 hr) [7] .
  The S.  typhimurium mutagenicity test  has  recently  been conducted
  on mercaptobenzothiazole with negative  results  (personal  communi-
  cation  with Paul Graham, Monsanto Company,  on  26 January  1979).
  This  information would most  likely  have changed the classifica-
  tion  given to mercaptobenzothiazole to  probable noncarcinogen by
  the criteria used in this report.

 [218]  Evaluation of Carcinogenic, Teratogenic,  and  Mutagenic
       Activities of Selected  Pesticides  and  Industrial Chemicals,
       Volume III.  National Technical  Information Service  No.
       PB 223 161, 1968.

 [219]  Evaluation of Carcinogenic, Teratogenic,  and  Mutagenic
       Activities of Selected  Pesticides  and  Industrial Chemicals,
       Volume II.  National Technical Information Service No.
       PB 223 160, 1968.
                                168

-------
                         Methyl Bromide


Methyl bromide has been tested on barley and is said to be a
methylating compound  [220] .  No other references were found on
the mutagenic or carcinogenic potential of methyl bromide, so it
has been placed on the probable noncarcinogen list.
 ;220] Ehrenberg,  L.,  et al.   On  the  Reaction  Kinetics  and  Muta-
      genic Activity  of Methylating  and  Beta-Halogenoethylating
      Gasoline Additives.   Radiat. Bot.,  14 (3) :185-194,  1974.
                                169

-------
                         Methyl Chloride


No data have been found indicating that methyl chloride  (chloro-
methane, CAS No. 74-87-3) is a carcinogen  (e.g., TOXLINE, CANCER-
LINE, and Reference 5).  However, it does appear to be a mutagen
to S. typhimuriurn [14].  Because of the close correlation between
mutagens and carcinogens, methyl chloride has been placed on the
possible carcinogen list.

Production and Persistence

It is estimated that 2.3 x 107 kg methyl chloride is emitted per
year from stationary sources [1].  Another estimate [44] is
7.6 x 106 kg/year released from a production of 2.1 x 108 kg.
Other production estimates are 2.1 x 106 kg, and 2.2 x 106 kg,
1.6 x 106 kg and 1.7 x 106 kg produced in 1974, 1975, and 1976,
with a projected growth of 6% per year [6, 32].  Reaction in the
atmosphere with the HO radical is slow, with a half-life of about
1 year  [44].  It takes 27 minutes for 50% of a 1-ppm water solu-
tion to evaporate at 25°C [33].  Methyl chloride has a boiling
point of -24°C and a vapor pressure of 3,800 mm (5 atm) at 20°C
and 2,150 mm (2.83 atm)  at 25°C [6, 33].
                                170

-------
                       Methyl Ethyl Ketone


Methyl ethyl ketone  (MEK, 2-butanone) is included on the NIOSH
Suspected Carcinogen List because of a teratogenic reference and
as a priority pollutant.  MEK does appear to be embryotoxic, feto-
toxic, and perhaps teratogenic when tested at high concentrations
(1,000-3,000 ppm)  [150,  221].  Rat feeding studies conducted in
1939 and 1940 were negative  [222, 223].  Mouse skin application
tests in 1965 of mixtures containing MEK were generally negative
in the absence of benzo(a)pyrene  [224].  MEK has also been  tested
on TA 1535, 1536, 1537,  and  1538  strains of S. typhimurium  bacte-
ria  (Ames Test) and on E. coli WP2-try mutagen tests with both
being negative [157] .  No other references could be found on TOX-
LINE or CANCERLINE indicating that MEK is a mutagen or a carcino-
gen.  It is considered a probable noncarcinogen for this project.
 [221] Embryo Toxicity  and  Feto  Toxicity of  Inhaled Carbon Tetra-
      chloride,  1,1-Dichloroethane,  and Methyl  Ethyl  Ketone in
      Rats.  Toxicol.  Appl.  Pharmacol.,  29(1):123, 1974.
 [222] Nakahara,  W.,  and  K. Mori.  Proc.  Imp.  Acad., Japan,
      15:278-281,  1939 (as cited  in  Reference 5).
 [223] Nakahara,  W.,  and  K. Mori.  Gann,  34:143-145, 1940  (as
      cited in  Reference 5).
 [224] Horton, A. W., et  al.   Cancer  Research, 25:1759-1763, 1965
       (as  cited in Reference  5).

                                171

-------
                       Methyl Methacrylate


Methyl methacrylate is on the NIOSH Suspected Carcinogen List
because of a paper which shows that 0.25 mg/kg of the compound
(1/5 LD50) caused 8% of the rat fetuses to have gross abnormal-
ities  (hemangiomas) but no skeletal malformation  [225] .  A search
of the literature could find no other references indicating methyl
methacrylate to be a mutagen or a carcinogen.  It is therefore
listed as a probable noncarcinogen for this project.
 [225] Singh, A. R., et al.  Embryonic-Fetal Toxicity and Tera-
      togenic Effects of a Group of Methacrylate Esters in Rats
      J. Dental Research, 51:1632-1638, 1972.
                                172

-------
               4,4'-Methylene Bis(2-chloroaniline)


4,4'-Methylene bis(2-chloroaniline) or MOCA  (CAS No. 101-14-4)
has been found to be a carcinogen in mice and rats after oral
administration and produces distant tumors in the rat after sub-
cutaneous administration  [226].  It is an OSHA regulated carcino-
gen [227].   Many other positive references are found in TOXLINE
and CANCERLINE and it is considered a probable carcinogen for
this project.

Production and Persistence

It is estimated that 4.5 x 104 kg is emitted per year from a
3 x 106 kg production  [56].  Other estimates of production are
1.5-2.5 x 106 kg in 1970  [226] and 3.5 x 106 kg in 1972  [6, 8,
226].  The reaction with the HO radical in the atmosphere is
estimated to yield a half-life of 12 hours  [8] or 1 day  [56],
while the 03 half-life is 1 day  [56] and the RO2 half-life is
39 days  [56].  It  is said to have a melting point of 110°C  [226]
and a negligible vapor pressure  [6].
 [226] IARC Monographs:   Evaluation  of the Carcinogenic Risk of
      Chemicals to Man,  Volume  4,  1974.   pp.  65-71.

 [227] OSHA Compliance Guide,  29 CFR Part 1910,  1978.
                                173

-------
                       Methylene Chloride


There are no positive data on methylene chloride  (dichloromethane)
in TOXLINE or CANCERLINE.   Interim results of carcinogenic tests
in a 2-year inhalation study involving nearly 2,000 animals ex-
posed to concentrations of methylene chloride as high as 3,500 ppm
were negative [228],   One  recent paper cites methylene chloride
as being positive in the Ames test [229].  Methylene chloride is
still considered a noncarcinogen for this project until further
testing is completed because of the negative NCI animal data.
[228]  Methylene Chloride Passes Early Tests.   Chem. Eng. News,
      55(19):6, 1977.

[229]  Mutation Research, Volume 53,  January 1978.


                               174

-------
                       Methylenedianiline


The IARC monograph [230] on methylenedianiline  [4,4-diaminodi-
phenyl methane, bis (p-aminophenyl)methane; CAS No. 101-77-9]
indicates both positive and negative data have been obtained
from animal testing of the compound.  Given orally to rats, it
was found to be noncarcinogenic.   Methylenedianiline is on the
NIOSH safety alert list because of some significant positive
results [231, 232] and it can at least be considered a possible
carcinogen for this project.

Production and Persistence

It is estimated that 2.6 x 104 kg is emitted per year from sta-
tionary sources [1].  The production has been estimated to be
5 x 105 kg, 7 x 105 kg, and 1 x 106 kg in 1965, 1966, and 1972
[230].  It has a melting point of 93°C and a boiling point of
231°C at 11 mm [33].
 [230] IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 4, 1974.  pp. 79-85.
 [231] Schoental, R.  Carcinogenic and Chronic Effects of 4,4'-
      Diaminodiphenylmethane, an Epoxyresin Hardener.  Nature,
      219:1162-1163, 1968.

 [232] Steinhoff, D., and E. Grundmann.  Zur Cancerogenen Wirkung
      von 4,4'-Diaminodiphenylmethan und 2,4'-Diaminodiphenyl-
      methan.  Naturwissenschaften, 57:247-248, 1970.
                               175

-------
                          Methylstyrene


One reference cited in the NIOSH Suspected Carcinogen List shows
methylstyrene to be a teratogen [233] .   Permissible exposure
limits have been determined for methylstyrene  [234] .  Application
of methylstyrene to rabbit [235] inhalation or rat skin  [235, 236]
demonstrated only a reversible  [236] irritating response to the
chemical.   Other toxic responses have been noted in rats, rabbits
[237], and housefly larvae [238],  but no indication of carcinogen
or mutagenic responses were found on TOXLINE or CANCERLINE.
[233] Gigiena i Sanitariya, 34:40, 1969.  (Translated in Hygiene
      and Sanitation.)

[234] Toxic Substances:   Proposed Occupational Safety and Health
      Standards for Alkyl Benzenes, Cyclohexane, Ketones, and
      Ozone.  Fed. Regist. 40(196):47262-47313, 1975.
[235] Effect of Alpha-Methylstyrene and Tert-Dodecyl Mercaptan on
      the Skin of Animals.  Vop. Gig. Tr. Profzabol., Mater.
      Nauch. Konf.; 1972.  pp.  247-249.

[236] Reversible Damage to the  Skin of Experimental Animals Sub-
      jected to the Inhalation  of Butadiene and Alpha-Methyl-
      styrene.  Mater.  Nauch. Sess., Posoyashck.  50-Letiyu
      Obrazov. SSSR, Omsk. Gas. Med. Inst.;  1972.  pp. 871-873.

[237] Effect of Isopropylbenzene and Alpha-Methylstyrene on Leu-
      copoiesis.  Farmakol. Toksikol., 35 (4):491-492, 1972.

[238] Effect of the Wastes from Phenol Production on Housefly
      Larvas.  Mater. Konf. Molodykh. Uch.  Stud., Posvyashch.
      50-Letiyu SSSR; 1973.  pp. 375-377.
                                176

-------
                           Morpholine


Morpholine  (diethyleneimide oxide, tetrahydro-1,4-isoxazine ;
CAS No. 110-91-8) is cited in one reference as  causing neoplastic
effects in the mouse after oral administration  of  6.33 g/kg over
28 weeks  [6].  This refers to a study  (with no  control animals)
in which 40 Swiss mice  (20M, 20F) were given neutralized morpho-
line in their food  [239].  After 40 weeks, 5 malignant lymphomas
and 5 lung adenomas were found in the  surviving 38 animals.
(When given in combination with sodium nitrite, many more tumors
were found.)

In another  study, 100 g/kg morpholine  as  0.5% of the diet for
rats produced no tumors, but 0.5% sodium  nitrite added gave 7
tumors  [240].  Many other studies have been conducted with  sodium
nitrite added to produce nitrosomorpholine in vivo and in vitro.
In Russian  studies, morpholine in the  air in 0.008-0.07 mg/1 con-
centrations for 4 months caused mutagenic chromosomal aberrations
in bone marrow cells in  rats  [241] and guinea pigs  [242] .   The
future classification of morpholine requires more  data, but for
this project it will be  considered a possible carcinogen.

Production  and Persistence

It is estimated that 1  x 107 kg is produced and 5.5 x 106 kg is
emitted per year  [6] .
 [239] Greenblatt, M.,  et  al.   J.  Natl.  Cancer  Inst.,  46(5):1029-
      1034, 1971  (as cited  in  Reference 5).
 [240] Sander, J., and  G.  Bunkle.   Z.  Krebsforsch,  73(l):54-66,
      1969.
 [241] Fomenko, V. N.,  and E. E.  Strekalova.  Mutagenic  Action  of
      Some Industrial  Poisons  as  a Function  of Concentration and
      Exposure Time.   Toksikol.  Nov.  Prom. Khim. Veshehestv.,
      13:51-57, 1973  (CA  79:143228).

 [242] Migukina, N. V.   Evaluation of  the Danger of Morpholine
      During Chronic Action.   Toksikol. Nov. Prom.  Khim.  Veshe-
      hestv., 13:92-100,  1973  (CA 79:143345).
                                177

-------
                             Naphtha


Naphtha (coal tar naphtha)  is cited in Reference 6 as a recognized
carcinogen.  Actually,  naphthas vary in composition depending on
their source, with coal tar naphtha being mainly benzene and its
homologs.   From other sources naphtha could be principally paraf-
fins, methanol and acetone, or gasoline.  Even as a mixture
naphtha is not found in Reference 5.  Of the primary ingredients
of naphtha, only benzene is a recognized carcinogen, and since
benzene is covered separately, naphtha will be dropped from
consideration.
                               178

-------
                         1-Naphthylamine


1-Naphthylamine (alpha-naphthylamine, CAS No. 134-32-7) no car-
cinogenic effect when given orally to hamsters, and both oral
and subcutaneous tests with mice gave inconclusive results  [243].
In dogs, it was demonstrated that 1-naphthylamine, if carcino-
genic at all, was less so than the 2-isomer  [243].  Other tests
on dogs  [26], hamsters, mice, rats, and rabbits  [112] show that
1-naphthylamine may be carcinogenic and that it is generally
contaminated with the 2-isomer, which is a potent carcinogen
[243, 244].  It is an OSHA regulated carcinogen  (Code of Federal
Regulations 29 CFR 1910.1004) whether or not it is truly a car-
cinogen  [244].  It is also positive on the S. typhimurium test
[52] and on an enhancement of viral transformation test  (personal
communication with B. C. Casto on 9 February 1978).  For these
reasons, it is considered a possible carcinogen for this project.

Production and Persistence

Production has been estimated to be 5 x 105 kg in 1963  [6] and
3.2 x 106 kg in 1974  [8].  It reacts with oxidizing materials in
the atmosphere  [6] and reacts with the HO radical in air with a
12-hour half-life  [8].  It has a boiling point of 300.8°C and a
vapor pressure of 1 mm at 104.3°C  [6].
 [243] IARC Monographs:  Evaluation of  the Carcinogenic  Risk  of
      Chemicals to Man, Volume  4, 1974.  pp.  87-96.

 [244] OSHA Compliance Guide,  29 CFR  Part 1910,  1004,  1978.
      pp. 298-300.
                                179

-------
                           Naphthalene


Naphthalene (CAS No. 91-20-3) has generally been negative when
given to rats and mice by various routes of administration
(including 10 g total oral dose over 33 months) with only a few
tumors reported by other authors in experiments without control
animals [5].   It is generally considered to be a noncarcinogen by
various authors [245].  It has been tested in G46 S. typhimuriuni
and K-12 E. coli strains [246] .  Another reference reports nega-
tive results  for S.  typhimurium strains TA 98, 100, 1535 and
1537 [52].   Naphthalene is considered a probable noncarcinogen
for this project.
[245]  Arcos,  J.  C.,  and M.  F. Argus.  Chemical Induction of Can-
      cer,  Volume IIA.   Academic Press, New York, 1974.  pp. 194,
      237,  and 278.

[246]  Kraemer, M.,  et al.   S. Typhimurium and E.  Coli to Detect
      Chemical Mutagens.   Naunyn-Schmiedebergs Arch. Pharmakol.,
      284:46R, 1974.
                               180

-------
                         Naphthoquinone


Naphthoquinone is on the NIOSH Suspected Carcinogen List because
of a 1940 Japanese reference  [62].  In this paper a-naphthoquinone
(in benzene)  painted daily on the backs of mice caused 3/77 skin
cancers and 11/77 papillomas compared to 0/46 skin cancers and
1/46 papillomas for benzene alone on mice surviving 200 days.
g-Naphthoquinone produced no cancers or papillomas out of 25 mice
surviving 200 days.

A survey of recent literature from TOXLINE, CANCERLIME, and Refer-
ence 5 found no pertinent references.  Since the only positive
reference is outdated and reports the use of benzene as the sol-
vent, naphthoquinone is being placed on the probable noncarcino-
gen list for this project.
                                181

-------
                   1-Naphthyl Methylcarbamate


The primary reference to this compound's carcinogenic potential
from a Russian journal has not been obtained.  Another Russian
reference from the same year [247] declares that 2-naphthyl
methylcarbamate is carcinogenic while 1-naphthyl methylcarbamate
is noncarcinogenic.  1-Naphthyl methylcarbamate tested on male and
female mice of two strains was found to be noncarcinogenic  [69].
No other references were found in CANCERLINE to indicate that this
chemical is a carcinogen.  There are negative mice feeding studies
(18 months) and rat intergastric studies reported  [5].  It is
probably a noncarcinogen based on the available literature.
 [247]  Zabezhinskiy, M. A.  Investigations on Possible Carcino-
       genic Effects of Beta-Sevin.  Vopr. Onkol.,  16 (11) : 106-107,
       1970.
                                182

-------
                          Nitrobenzene
Although on structural basis nitrobenzene  (CAS No. 98-95-3) has
been predicted to be a carcinogen, there was no positive indica-
tion from actual tests of the chemical cited in "Air Pollution
Assessment of Nitrobenzene"  [248] or on CANCERLINE or TOXLINE.
It has been reported to induce sex-linked recessive lethal muta-
tions in Drosophila melanogaster when administered as a vapor for
8-10 days [32].   With only one in vitro positive test reported,
nitrobenzene will be considered a noncarcinogen (with some posi-
tive data) for this project.
[248] Dorigan, J., and J. Hushon.  Air Pollution Assessment of
      Nitrobenzene.  National Technical Information Service No
      PB 257 776, May 1976.
                                183

-------
                           Nitrophenol


No data on the carcinogenicity of nitrophenols could be found on
CANCERLINE or TOXLINE,  but p-nitrophenol has been found to be
mutagenic by one test system and nonmutagenic by five other test
systems [18].  When comparing S.  typhimurium test results with
other systems, Ames classified nitrophenol as a nonmutagen [52].
For this project, nitrophenols will be classed as probable non-
carcinogens .
                               184

-------
                      Nitrosodimethylamine


There are many data showing nitrosodimethylamine  (dimethylnitroso-
amine)  to be a potent carcinogen  [249].  It has,  therefore, been
placed on the probable carcinogen list for this project.  In the
final selection of carcinogens, however, it may not be advantage-
ous to select this compound.  This is because nitrosodimethylamine
rapidly decomposes in sunlight  [250] , under normal conditions is
of no significance as an air pollutant  [250], and has generally
been found only in the air near certain manufacturing plants which
had (now repaired) leaks in their systems  [251].

Production and Persistence

Nitrosodimethylamine is emitted in less than 100-kg year quanti-
ties from the dimethylhydrazine stationary sources  [1].  One
estimated of production is less than 450 kg/year  [8].  Photolysis
of nitrosodimethylamine is reported  to be rapid with a half-life
of less than 1 hour  [8].  It has  a boiling point  of 152°C  [33].
 [249]  IARC Monographs:   Evaluation  of  the  Carcinogenic  Risk  of
       Chemicals to Man,  Volume  1, 1972.  pp.  95-106.

 [250]  Bretschneider,  K.,  and  J.  Matz.   Occurrence  and Analysis  of
       Nitrosamines in Air.  IARC Sci.  Pub.  No.  14,  1976.   pp.  395-
       399.
 [251]  Fine,  D. H., et al.   N-Nitroso Compounds  in  Air and  Water.
       IARC Sci. Pub.  No.  14,  1976.  pp.  401-408.
                                185

-------
                       Nitrochlorobenzene
Nitrochlorobenzene (chloronitrobenzene)  has been found to mutate
S.  typhimurium [252]  and is indicated as a carcinogen causing
neoplasms in another reference's summary sheets while listed as
not tested in an appendix to the same reference [6].   For this
project it will be considered a possible carcinogen.

Production and Persistence

It is estimated that 3 x 102 kg nitrochlorobenzene is emitted per
year from stationary sources [1].   An estimate of production is
6.4 x 107 kg of each of the isomers produced in 1967  [6].  Nitro-
chlorobenzene reacts with oxidizing materials in the atmosphere
[6].   In the soil, microflora decomposes this chemical in 64 days
[1].   The m-, p-,  and o-isomers have boiling points of 236, 242,
and 245°C with a vapor pressure of 10 mm at 25°C [33] .
[252]  Tardiff,  R.  G.,  et al.   Halogenated Organics in Tap Water:
      A Toxicological  Evaluation.  In:  The Environmental Impact
      of Water  Chlorination,  National Technical Information
      Service No.  CONF 751096,  1976.   pp. 213-228.
                                186

-------
                            Parathion
Nothing was found in CANCERLINE to indicate that parathion is a
mutagen or carcinogen.  The NIOSH Suspected Carcinogen List refer-
ence cites parathion as being a slight teratogen only when given
in sufficient quantitiy as to cause toxic poisioning to be appar-
ent in the dams  [134].  It has been found to be nonmutagenic by
several different in vitro tests  [18], but does cause an anti-
mitotic action in cells [171].  It is therefore classified as a
probable noncarcinogen for this project.
                                187

-------
                             Pentane
Although n-pentane is cited as a carcinogen in one reference  [6],
no primary references could be found to substantiate this allega-
tion in TOXLINE,  CANCERLINE,  or Reference 5.  It is said that
aliphatic hydrocarbons may be cocarcinogens [4].  For this project
pentane will be considered a noncarcinogen.
                               188

-------
                        Pentachlorophenol


Pentachlorophenol  (CAS No. 87-86-5) has been found negative in
some relatively short studies on rabbit skin and orally in rats
and cats [26].  More recently it has been found negative in two
strains of mice both orally and subcutaneously  [69].  Penta-
chlorophenol is also negative in Drosophila tests  [253], in a
host-mediated assay mediated assay in mice  [254] , and in other
microbial systems  [152].

Some authors consider pentachlorophenol a known mutagen [255],
and there are other positive as well as negative short-term tests
reported [18].  It is also positive at the  100-yg level in the
hamster embryo adenovirus enchancement assay  (personal communica-
tion with B. C. Casto on 17 February 1978).  For these reasons,
pentachlorophenol will be considered a possible carcinogen for
this project for the first round of evaluations.

Production and Persistence

One estimate of production is 2.1 x 107 kg  (1969 capacity) and a
consumption of 2.3 x 107 kg in 1975  [6],  In the soil it degrades
completely in >72 days  [33].  It has a boiling point of 310°C and
a vapor pressure of 1.1 x 10~4 mm at 20°C [33].
 [253] Vogel, E., and  J.  L.  R.  Chandler.   Mutagenicity  Testing  of
      Cyclamate and Some Pesticides  in  Drosophila  Melanogaster.
      Experientia, 30 (6) :621-623,  1974.

 [254] Buselmaier, W., et al.   Comparative Investigations  on  the
      Mutagenicity of Pesticides  in  Mammalian  Test Systems.
      Mutat. Res., 21(l):25-26,  1973.

 [255] Daugherty, R. C.,  and K. Piotrowska.   Screening  by  Negative
      Chemical lonization Mass Spectrometry  for  Environmental
      Contamination with Toxic Residues:   Application  to  Human
      Urines.  Proc.  Natl.  Acad.  Sci.,  73 (6):1777-1781,  1976.
                                189

-------
                             Phenol
Phenol (hydroxybenzene, CAS No. 108-95-2) has been reported to
give rise to papillomas after administration on mouse skin  [153,
256].   Phenol has also been reported negative by injection and
negative on the skin of mice [5].   It has recently been given in
combination with other chemicals [5].  In mutagenicity tests,
phenol has been found to be mutagenic to Drosophila, revert E.
coli to streptomycin independence,  and induce chromosome breakage
in the root tip of Allium cepa while being inactive in reverting
Neurospora arassa to adenine prototrophy [32].   Phenol is also
said to cause second chromosome breaks in Drosophila and to cause
chromosome breaks in Vicia and Allium sativum,  and it is terato-
genic in chickens [44].  One must also remember, however, that
normal adults excrete approximately 30 mg of volatile phenols per
day in their urine (mainly p-cresol and phenol)  produced by gut
bacterial metabolism of tyrosine [86].  Phenol has tested nega-
tive in a micronucleus test [257].   The only positive animal
tests were conducted in the fifties with later negative results.
The positive in vitro tests are with systems which have not been
extensively evaluated.   Although it is a borderline chemical,
phenol will be considered a probable noncarcinogen  (with some
positive data) for this project.
[256]  Salaman,  M.  H.,  and O.  M.  Glendenning.  Brit. J. Cancer,
      11:434-444,  1957.

[257]  Hossak,  D.  J.,  and J.  C.  Richardson.  Examination of the
      Potential Mutagenicity of  Hair Dye Constituents Using the
      Micronucleus Test.  Experientia, 33 (3) :377-378, 1977.
                               190

-------
                    Polychlorinated Biphenyls

                               ft
Polychlorinated biphenyls  (PCB, chlorinated diphenyls, Aroclors,
Kanechlors) have been cited extensively in the literature as
carcinogens [258, 259].  On close inspection, many of the carci-
nogenicity studies on PCB's have been questionable  [5, 260] or
negative [261], and the increase in cancer among PCB workers
has been questioned [262].   The latest NCI study of PCB's was
negative, but they concluded that from the open literature PCB's
are probably promoters of carcinogenesis.  The PCB's fall on the
border between possible and probable carcinogens using the crite-
ria for this project.   Because of the positive animal studies  [2,
258], they will be classed as a probable carcinogen for this
project.

Production and Persistence

It is estimated that 1.8 x 104 kg is emitted per year [1].  Other
estimates of production are 1.4 x 107 kg, 2.5 x 106 kg, and
1.8 x 107 kg  (1974) [6, 8,  56].  Production of PCB's has been
phased out within the last year, so emissions should have dropped
to zero.  PCB's are essentially nonvolatile, but evaporation to
the atmosphere is thought to be important  [8].  Reaction with HO
radical predicts a half-life of 26 days [56].  PCB's have a boil-
ing point of 365-390°C and a vapor pressure less than 1 mm at
25°C  [6] .
 [258] IARC Monographs:  Evaluation of' the Carcinogenic Risk of
      Chemicals to Man, Volume  7, 1974.  pp.  261-289-

 [259] Lloyd, J. W., et al.  Polychlorinated Biphenyls.   J. Occup
      Med., 18 (2):109-113,  1976.
 [260] Andrews, E.  J., et al.  PCB Diet.  Science,  180 (4083) :255-
      257, 1973.
 [261] Ito, N., et  al.  Histopathological Studies on  Liver Tumori-
      genesis  in Rats Treated with Polychlorinated Biphenyls.
      Gann, 65 (6):545-549,  1974.
 [262] Lawrence, C.  PCB? and Melanoma (letter to the editor).
      N. Engl. J.  Med., 296 (2) :108-109,  1977.


                                191

-------
                            Propanol


In 1939 and 1940,  propanol (propyl alcohol, CAS No. 71-23-8) was
found noncarcinogenic in rat feeding studies [222, 223].  The
only current references which could be found were Gibel et al.
who refer to tumor formation after oral (50 g/kg) and subcutane-
ous (6 g/kg) administration of propanol to rats  [263] and an E.
coli test [264].  The studies which have been conducted on iso-
propanol have been negative [265].  Propanol will be considered
a probable noncarcinogen (with some significant positive data)
for this project.
[263]  Gibel,  W.,  et al.   Experimental Study on Cancerogenic
      Activity of Propanol-1,  2-Methylpropanol-l,  and 3-Methyl-
      butanol.  Arch.  Geschwulstforsch, 45(1):19-24, 1975.

[264]  Gibel,  W.,  et al.   Studies on the Toxicity and Mutagenicity
      of Single  Fusel  Oil Components on E.  Coli.  Acta Biol. Med.
      Ger.,  23:843-852,  1969.

[265]  IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals  to Man,  Volume 15, 1977.  pp. 223-243.
                                192

-------
                         Propylene Oxide


Propylene oxide  (methyloxirane, 1,2-epoxypropane; CAS No. 75-56-9)
has been reported to cause local  sarcomas  in a limited number
of rats after subcutaneous injection  [266].  It was negative in
relatively short-term  (^200 days) studies  in rats, guinea pigs,
rabbits and monkeys given propylene oxide  by inhalation  [266,
267].  By in vitro tests, transformation of hamster cells  [96]
occurred at 250 mg/ml  (personal communication with B. C. Casto
on 9 February 1978).   It is also  reported  to cause reversion to
adenine, prototrophy in Neurospora cvassa, and recessive lethal
mutation in Drosophila melanogaster  [32].  For this project it
will be considered a possible  carcinogen.

Production and Persistence

It is estimated  that 4.4 x 106 kg propylene oxide is emitted per
year  [1].  Other production estimates  include 7.5 x 108 kg per
year  [6], 8.0 x  108 kg  (1974)  [8], 8.0 x 10s kg  (1975)  [266], and
7.0 x 108 kg  (1975)  [32] with  U.S. consumption predicted to grow
by 9-10.5% a year  from 1975 to 1980  [32].  If dispersed in the
atmosphere, epoxides would be  oxidized by  HO radicals with a
half-life of 3-11  hours  [8].   The rate constant  and half-life
for HO radical reaction predict a 23-hour  half-life for aliphatic
epoxides  [32].   Propylene oxide has a  boiling point of 33.9°C and
a vapor pressure of 596 mm at  25°C  [6] .
 [266]  IARC Monographs:   Evaluation of the Carcinogenic Risk of
       Chemicals  to  Man,  Volume 11, 1976.   pp.  191-199.

 [267]  Rowe,  L. K.,  et  al.   Toxicity of Propylene Oxide Determined
       on  Experimental  Animals.  Arch. Industr.  Hlth.,  13:228-236,
       1956.
                                193

-------
                             Pyrene


Pyrene (CAS No. 129-00-0)  has generally been tested on mouse skin
with negative results [5].  It has also been reported negative on
mouse skin followed by croton oil or preceded by benzo(a)pyrene
[5].  It is usually considered to be noncarcinogenic  [52, 268]
and has been reported as nonmutagenic to S. typhimurium strains
TA 98, 100, 1535 and 1537  [52].  It is considered a noncarcinogen
for this project.
[268]  Arcos,  J.  G.,  and  M.  F.  Argus.   Chemical Induction of
      Cancer,  Volume IIA, Academic  Press,  New York,  1974.
      pp.  210,  237.
                                194

-------
                           Sorbic Acid
Sorbic acid (2,4-hexadienoic acid, CAS No. 110-44-1) is a widely
used food preservative.  In 1966 and 1968, Dickens et al. re-
ported several rat studies with sorbic acid.  In these test  (using
6-12 rats) sorbic acid injected subcutaneously at 2 mg/injection
in oil or water sometimes caused local fibrosarcomas at the  injec-
tion site [269-271].  Given in the drinking water at 0.1 g/1, no
effects were seen [271].  It is now known that the pH of the
injected solution may cause local fibrosarcomas in some strains
of rats.  In more recent dose response studies, rats  [272] and
mice  [273]  (groups of ^100 animals) were given 0%, 1.5%, or  10%
of their diet as sorbic acid with no carcinogenic response.  Also
sorbic acid with 1,000 ppm parasorbic acid gave no carcinogenic
response  [274].  Several in vitro tests  (e.g., B. subtilis]  have
been negative for sorbic acid but positive for reaction products
of sorbic acid and sodium nitrite  [275].  Better subcutaneous
tests should be conducted on sorbic acid, but the negative results
on the recent large-scale feeding tests and negative in vitro re-
sults suggest that sorbic acid should be considered a noncargino-
gen at the present time.
 [269] Dickens, F., et al.   Brit.  J.  Cancer,  20:134-144,  1966.

 [270] Dickens, F., and  H.  B. Wayforth.   Brit.  Emp.  Cane.  Camp.,
      46:108, 1968.
 [271] Dickens, F., et al.   Brit.  J.  Cancer,  22:762-768,  1968.

 [272] Grant,  I. F., et  al.   Long-Term Toxicity of  Sorbic  Acid  in
      the Rat.  Food Cosmet. Toxicol.,  13(l):31-45,  1975.

 [273] Hendy,  R. J., et  al.   Long-Term Toxicity Studies  of Sorbic
      Acid in Mice.  Food  Cosmet.  Toxicol.,  14 (5) :381-386,  1976.

 [274] Mason,  P. L., et  al.   Long-Term Toxicity of  Parasorbic Acid
      in Rats.  Food Cosmet. Toxicol.,  14 (5) :387-394,  1976.

 [275] Kada, T.  Mutagenicity and  Carcinogenicity  Screening of
      Food Additives by the Rec-Assay and  Reversion Procedures.
      IARC Sci. Pub. No. 12, 1976.   pp.  105-115.
                                195

-------
                             Styrene


Styrene (vinyl benzene, CAS No. 100-42-5) has been found to be
both positive [276, 277] and negative  [278] on the S. typhimurium
mutagen test after activation with S-9 microsomes.  Without S-9
activation it has been found negative by this test [276, 278] .
In other systems, styrene was found positive on a host-mediated
forward mutation, gene-conversion yeast system but negative in
this system with microsomes only  (not host-mediated).  It was
negative on a Chinese hamster cell test  [279], in Drosophila
melanogaster and S. pombe mutation tests [32], and in enhancement
of viral transformation tests  (personal communication with B. C.
Casto on 9 February 1978).   It would thus appear that a metabolic
product of styrene is a weak mutagen and styrene should probably
be considered a possible carcinogen.

Production and Persistence

It is estimated that 5.6 x 106 kg styrene is emitted per year
from stationary sources  [1].  Another source estimates 2.0 x 109
kg (1975)  produced [6].  It has a 1.28 relative chemical reactivity
in the atmosphere  (where methane is zero, butane is  1.27,
2-pentane is 1.58 and 2-butene is 15.5)  [33, 280].   Styrene has a
145.2°C boiling point and a vapor pressure of 5 mm at 20°C  [33].
 [276] DeMeester, C., et al.  Mutagenic Activity of Styrene and
      Styrene Oxide.  Arch. Int. Physiol. Biochim., 85(2):398-
      399, 1977.

 [277] Vainio, H., et al.  A Study on the Mutagenic Activity of
      Styrene and Styrene Oxide.  Scand. J. Work Environ. Health,
      2 (3) :147-151, 1976.

 [278] Stolz, D. R.  Mutagenicity Testing of Styrene and Styrene
      Epoxide in Salmonella Typhimurium.  Bull. Environ. Contam.
      Toxicol., 17 (6) :739-742, 1977.

 [279] Loprieno, N., et al.  Mutagenicity of Industrial Compounds:
      Styrene and Its Possible Metabolite Styrene Oxide.  Mutat.
      Res.,  40 (4) :317-324, 1976.

 [280] Yeung, C. K. K.,  and C. R. Phillips.  Estimation of Physio-
      logical Smog Sympton Potential from Chemical Reactivity of
      Hydrocarbons.  Atm. Environ., 7, 1973.
                               196

-------
                            Sulfolane
Sulfolane (tetrahydrothiophene-1,1-dioxide, CAS No. 126-33-0)  was
1 of the 80 chemicals selected as having the greatest potential
environmental effects [7].  Carcinogenicity and mutagenicity were
not cited as reasons for its selection.  No data could be found
in any of the references searched pertaining to mutagenicity or
carcinogenicity of this chemical.   It is considered a probable
noncarcinogen for this project.
                                197

-------
                        Tetrabromoethane


Tetrabromoethane (CAS No.  79-27-6)  was 1 of 80 chemicals having
potential for environmental effects [56].   It has tested negative
in some short-term (92 day),  limited-exposure (15 min/day) tests
on rats, mice, rabbits and guinea pigs  [281].  It has tested posi-
tive in an E.  ooli (pol A+, pol A~) differential growth mutagen
test but negative in S.  typhimurium strains TA 1530 and TA 1535
[282, 283].  With only one in vitro positive test (which has not
been extensively validated) tetrabromoethane will be considered a
probable noncarcinogen for this project.
 [281]  Gray, A.  W.  A.   Arch.  Ind.  Hyg.,  2:407-419,  1950 (as
       cited in  Reference  5) .

 [282]  Brem, H.,  et al.  The  Mutagenicity and DNA-Modifying Effect
       of  Haloalkanes.   Cancer  Res.,  34:2576-2579,  1974.

 [283]  Rosenkranz,  H.  S.   Mutagenicity  and DNA-Modifying Activity:
       A Comparison of Two Microbial  Assays.   Mutat.  Res.,  41(1):
       61-70,  1976.
                                198

-------
                        Tetrachloroethane
1,1,2,2-Tetrachloroethane  (CAS No. 79-34-5) has been found to be
mutagenic in the S. typhimurium system for TA 1530 and TA 1535
strains  [282].  It has been cited as a carcinogen based on a
National Cancer Institute bioassay  [284] where it was found to
be a carcinogen for mice but not for rats  [285].  It is therefore
considered a probable carcinogen for this project.

Production and Persistence

It is estimated that 0.4 x 103 kg is emitted per year from sta-
tionary  sources  (in making trichloroethylene from ethylene)  [1].
Evaporation of 50% from a 1-ppm solution of water at 25°C will
occur in 56 minutes  [33].  It has a boiling point of 146.4°C and
a vapor pressure of 5 mm at 20°C  [33] .  Water solubility is 2.9  g/1
at 20°C  [33] .
 [284] Kraybill, H. F.   Origin,  Classification,  and Distribution
      of Chemicals in  Drinking  Water  with an Assessment  of  their
      Carcinogenic Potential.   In:  The  Environmental  Impact of
      Water Chlorination,  National  Technical Information Service
      No. CONF  751096,  1976.  p.  229.
 [285] Chemical  Regulation  Reporter, 1(51):1861,  1978.


                                199

-------
                       Tetrachloroethylene


Reference 286 cites extensive toxicological data but reports no
evidence of carcinogenicity,  mutagenicity or teratogenicity for
tetrachloroethylene (perchloroethylene, CAS No. 127-18-4) in
humans.   Also no difference in the incidence of tumors was ob-
served between control and experimental rats exposed to 300 or
600 ppm of tetrachloroethylene.  A recent report by NCI, however,
has shown tetrachloroethylene to be a liver carcinogen in B6C3F1
of both sexes [287].  Tetrachloroethylene has, therefore, been
assigned to the probable carcinogen list.

Production and Persistence

It is estimated that 7.8 x 107 kg tetrachloroethylene is emitted
per year from stationary sources with solvent evaporation from
degreasing operations accounting for better than 99% of that quan-
tity [1].  Other estimates of production are 3.0 x 10s kg (1975)
[6], 3.3 x 10s kg produced and 2.6 x 10s kg released  [7], and
production of 3.3 x 10s kg, 3.1 x 108 kg, and 3.0 x 10s kg in
1974, 1975, and 1976 [32].  A 1976 forecast projected a yearly
growth of 3-4% but in light of the NCI carcinogen study, lower
standards for occupational exposure from NIOSH, and a decrease
in fluorocarbon use, the production of tetrachloroethylene is
expected to decrease [32].  It is not photoactive and has an
expected HO radical reaction half-life of 8 days [7].  Another
reference cites photodegradation with a half-life of 2 days [286],
Evaporation of 50% from a 1-ppm water solution at 27°C will take
only 24-28 minutes  [33].  It has a boiling point of 121.2°C and
a vapor pressure of 14 mm at 20°C [33].
[286]  Fuller,  B. B.  Air Pollution Assessment of Tetrachloro-
      ethylene.   National Technical Information Service No.
      PB 256 731, 1976.  99 pp.

[287]  Bioassay of Tetrachloroethylene for Possible Carcinoge-
      nicity,  CAS No.  127-18-4.  National Technical Information
      Service  No. PB 272 940,  1977.
                               200

-------
                         Tetraethyl Lead


Tetraethyl lead  (tetraethyl plumbane, CAS No.  78-00-2) has been
found to induce lymphomas when injected subcutaneously into neo-
natal mice [288] although the significance of  this test has been
questioned [289] .  Oral doses were not found to be teratogenic
[290],  and an epidemiological study found no health hazard from
occupational exposure  [291].

Tetraethyl lead has been found to cause DNA fragmentation and to
enhance viral transformation in hamster embryo at the 12.5-yg
level  (personal communication with B.  C. Casto on 17 February 1978)
Tetraethyl lead is considered a possible carcinogen for this
project.

Production and Persistence

One estimate of release to the environment is  1.3 x 10s kg per
year [44] from a production of 1.4 x  108 kg.   The release figure
notes that most of this is through use in gasoline where it is
converted to lead halides and some lead phosphates  [44].  Another
set of figures cites a release of 6.6 x 106 kg from a production
of 1.6 x 10s kg  in 1973  [6].  The 1971 production has been esti-
mated to be 2.4  x 10s kg  []89].  The  production of tetraethyl
lead is expected to decrease rapidly  from these figures because
of regulations requiring less lead in gasoline  [289].  In the
air it has a half-life of 2-3 days from reactions with HO and 03
radicals [6,  44].  It has a boiling point of 200°C  (decomposes)
and a vapor pressure of 0.15 mm at 20°C [6, 33].
 [288] Epstein, S. S., and N. Mantel.  Carcinogenicity  of Tetra-
      ethyl Lead.  Experientia,  24 (6) :580-581,  1968.

 [289] IARC Monographs:  Evaluation of the  Carcinogenic Risk  of
      Chemicals to Man, Volume  2, 1973.  pp.  150-160.

 [290] Kennedy, G. L., et al.  Teratogenic  Evaluation of Lead Com-
      pounds  in Mice and Rats.   Food Cosmet.  Toxicol.,  3 (6): 629-
      632, 1975.
 [291] Robinson, T. R.  Health,  How Can  It  Be  Measured. In:   HEW
      Publ.  (NIOSH)  76-134,  1976.  pp.  114-130.
                                201

-------
                             Toluene
An extensive search of CANCERLINE and TOXLINE along with the NTIS
document "Air Pollution Assessment of Toluene"  [292] and the
Stanford Research Institute hazard priority ranking [7] failed
to find data which would indicate that toluene is a carcinogen.
It tested negative [46] in a differential growth mutagen test
using E. coli (pol A)  and will be considered a noncarcinogen for
this project.
.292]  Walker,  P.   Air Pollution Assessment of Toluene.  National
      Technical Information Service No.  PB 256 735,  1976.
                              202

-------
                      Toluene Diisocyanate


There are no data on TOXLINE or CANCERLINE to indicate that
toluene diisocyanate is a mutagen or a carcinogen.
                               203

-------
                         Toluenediamine
Toluenediamine (toluene-2,4-diamine, CAS No. 95-80-7), generally
used as a hair dye, has been found by several studies to be non-
carcinogenic when applied to the skin of mice [126, 293] and rats
[125], although the same data can be interpreted to show increased
lung tumors and total tumors in the test groups  [294] .  Toluene-
diamine has been reported to produce hepatomas in rats when fed
at 0.1% of diet for 35 weeks [295] or 11 g/kg for 36 weeks  [296].
In rats, 280 mg/kg (35 weeks) subcutaneously is reported to cause
neoplasms  [6].  It has also been found to cause morphological
transformation in primary Syrian hamster embryo cells.  It also
mutates S.  typhimurium strains TA 1538 and TA 98 at 0.5 yg/ml
when activated with the S9  microsomes [295, 297].  With positive
in vivo and in vitro  tests, toluenediamine will be considered a
probable carcinogen for this project.

Production and Persistence

One estimate of production  is 2.9 x 107 kg per year with 0.015 as
a fraction of production loss [6].  It has a boiling point of
292°C and a vapor pressure  of 1 mm at 106.5°C [6].
 [293] Giles, A. L.,  et al.  Dermal Carcinogenicity Study by
      Mouse-Skin Painting with 2,4-Toluenediamine Alone or in
      Representative Hair Dye Formulations.  J. Toxicol. Environ.
      Health, 1(3):433-440, 1976.

 [294] Bridges, B. A., and M. H. Green.  Carcinogenicity of Hair
      Dyes by Skin Painting in Mice  (letter to editor).  J.
      Toxicol. Environ. Health, 2(1):251-252, 1976.

 [295] Shah, M. J.,  et al.  Comparative Studies of Bacterial Muta-
      tion and Hamster Cell Transformation Induced by  2,4-Toluene-
      diamine  (Meeting Abstract).   Proc. Am. Assoc. Cancer Res.,
      18:22, 1977.

 [296] Cancer Research, 29:1137, 1969.

 [297] Pienta, R. J., et al.  Correlation of Bacterial  Mutagenicity
      and Hamster Cell Transformations with Tumorigenicity Induced
      by 2,4-Toluenediamine.  Cancer Lett.  (Amsterdam), 3(1/2):
      45-52, 1977.
                               204

-------
                            Toxaphene


No significant data were found to indicate that toxaphene is a
mutagen or a carcinogen.  It tests negative on the dominant
lethal test for mice  [30].  It has been placed on the probable
noncarcinogen list for this project.
                               205

-------
                           Trichlorfon
Trichlorfon has been found to be carcinogenic to mice, rats, and
cats given orally,  subcutaneously,  cutaneously, or intermuscularly
[3, 5].   It has also been found to  be mutagenic by at least five
different test systems [3, 5].  It  is, therefore, to be considered
a probable carcinogen.

Production and Persistence

It is estimated that 100 kg/year of trichlorfon is emitted from
stationary sources  [1].
                                206

-------
                         Trichloroethane
A National Cancer Institute bioassay of 1,1,1-trichloroethane
found no correlation between this chemical and any cancers which
developed in the control versus the test rats and mice  [298] .
It was negative on an enhancement of viral transformation test
(personal communication with B. C. Casto on 9 February 1978).
It has been placed on the noncarcinogen list for this project.
 [298]  Bioassay of  1,1,1-Trichloroethane for  Possible Carcinogen-
       icity.   Carcinog.  Tech.  Rep.  Serv.  - Natl.  Cancer  Inst.
       (U.S.);  ISS  NCI-CG-TR-3,  1975.   70  pp.
                                207

-------
                        Trichloroethylene


Trichloroethylene (trichloroethene, TCE; CAS No. 79-01-6) has
been found to induce a high incidence of hepatocellular carcinoma
in B6C3TI1 mice of both sexes by NCI [299] .  It has also been
found to be weakly mutagenic in E.  ooli and to the TA 100 strain
of c.  typhimurium (0.8-2.0% vapor dose response when exposed 1
hour)  in the presence of activated microsomes  [32].  A review of
the production, uses and environmental effects has been compiled
by Fishbein  [75].  TCE is considered a probable carcinogen for
this project.

Production and Persistence

It is estimated that 1.6 x 10s kg of TCE is emitted per year with
95% of that coming from solvent evaporation in degreasing opera-
tions [1].  Another estimate is a production of 1.93 x 108 kg
with 1.95 x 108 kg released [7].  Other production estimates [6,
8] include 1.8 x 108 kg (1974) and 1.3 x 10s kg/year, with about
60% of the production released to the environment [300].  Produc-
tion has also been reported to be 1.8 x 108 kg  (1974), 1.3 x 108
(1975) and 1.4 x 10B kg (1976) with a 1% decline predicted for
future years  [32].  Since that prediction, OSHA has lowered the
standard for occupational exposure and NCI found that TCE causes
tumors in mice which will mean a much greater decline in the ex-
pected production [32].  TCE has a high atmospheric photodegrada-
tion rate  with a half-life of 0.3 day at sea level  [300].  Other
sources predict atmospheric reaction with the HO radical with a
half-life of 36 hours  [8]  or less than 50 hours [7].  With its
high volatility and low water solubility it is expected to fairly
rapidly migrate into the atmosphere.  In fact 50% of a 1-ppm
solution will evaporate from water at 25°C in 19-24 minutes  [33].
Its boiling point is 86.7°C and it has a vapor pressure of 60 mm
at 20°C  [33].
 [299] Carcinogenesis Bioassay of Trichloroethylene, CAS No. 79-
      01-6.  National Cancer Institute Carcinogenesis Technical
      Report Services, Number 2, February 1976  (NCI-CG-TR-2).

 [300] Fuller, B. B.  Air Pollution Assessment of Trichloroethyl-
      ene.  National Technical Information Service No. PB  256
      730, 1976.
                               208

-------
                     Trichlorofluoromethane


In mice, trichlorofluoromethane  (Freon-11, F-ll) in combination
with the insecticidal synergist piperonyl butoxide increased the
incidence of malignant hepatomas while Freon-11 by itself was
found to be noncarcinogenic  [301] .  No other carcinogenic data
were found on Freon-11, and  it has been found to be nonmutagenic
in S. typhimurium tests with and without microsomal activation
[302].  Preliminary results  from an NCI bioassay show no differ-
ence between control and treated male or female rats  [303].  It
is probably not a carcinogen.
 [301] Epstein, S. S., et al.  Synergistic Toxicity and Carcino-
      genicity of "Freons" and Piperonyl Butoxide.  Nature, 214
      526-528, 1967.
 [302] Uehleke, H., et al.  Metabolic Activation of Haloalkanes
      and Tests in Vitro for Mutagenicity-  Xenobiotica, 7(7):
      393-400, 1977.
 [303] NCI Preliminary data on trichlorofluoromethane, Nov. 27,
      1976.
                               209

-------
                         Trichlorophenol


Trichlorophenol (2,4,6-trichlorophenol,  Dowicide 2S; CAS No. 88-
06-2)  has been found to be a carcinogen in mice when given orally
but not subcutaneously [69, 77].  Seven/seventy-two hepatomas,
6/72 pulmonary adenomas,  and 7/72 reticulum cell sarcomas were
found.  (2,4,5-Trichlorophenol was only evaluated by the subcu-
taneous route [69] and was found negative by this route of admin-
istration, as was 2,4,6-trichlorophenol.)  Trichlorophenol may
cause abnormal pollen  in broad bean plants [304].  No other
pertinent literature references were found on TOXLINE or CANCER-
LINE to substantiate or refute the carcinogenic potential of
trichlorophenol.  It has been placed on the possible carcinogen
list for this project.

Production and Persistence

It is estimated that 5 x 102 kg trichlorophenol is emitted from
stationary sources per year [1].  Since this is used as a pesti-
cide,  nonstationary sources (or total production) should be con-
sidered.  It completely disappears in soil suspensions in 5 days
[33].   Trichlorophenol (2,4,6) has a boiling point of 244.5°C
and a solubility of 800 mg/1 at 25°C [33].
 '304] Cytological Effects of Pesticides.  V.  Effects of Some
      Herbicides on Vioia Faba.  Cytologia, 39 (4) :663-643,  1974
                                210

-------
                           Urethane
Urethane  (ethyl carbamate, CAS No. 51-79-6) has been shown to be
carcinogenic in mice, rats and hamsters following administration
by the oral, inhalation, subcutaneous or intraperitoneal routes
[305].  It generally causes lung tumors, lymphomas, hepatomas,
melanomas, and vascular tumors.  With all of these positive data,
urethane is considered a probable carcinogen for this project.

Production and Persistence

The only production data which could be found cited from one U.S.
producing company with no data given and production below 454 kg
from a second company  [305].  It has a boiling point of 183°C,
sublimes at 102°C and 54 mm Hg, and is volatile at room tempera-
ture  [305].
3The name urethane is sometimes applied to high molecular weight
 polyurethanes used as foams, elastomers and coatings.  Such
 products are not made from the chemical urethane and do not
 generate it on decomposition.
 [305] IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume  7, 1974.  pp.  111-140.
                                211

-------
                          Vinyl Acetate


Vinyl acetate (CAS No.  108-05-4)  has been found to be noncarcin-
ogenic in rats at 2,500 ppm for 4 hr/day for 12 months by
C. Maltoni [5].   It has also been found negative on mouse skin
[306], mouse sebaceous  glands  [307], and S.  typhimurium tests
[52, 97,  146].  Both commercial vinyl acetate  [96] and repeated
tests of purified vinyl acetate  (personal communication with
B. C. Casto on 9 February 1978) have been found to be mutagenic
at a level of 150 yg/ml in viral transformation of Syrian hamster
cells.  Because of this enhanced transformation, vinyl acetate
will be considered a possible carcinogen for this project for
the first round of evaluations.

Production and Persistence

It is estimated that 6.8 x 105 kg is emitted per year from sta-
tionary sources  [1].   Another estimate is a release of 7.8 x 106
kg from a production of 5.5 x 108 kg [6].  It reacts with oxidiz-
ing materials in the atmosphere  [6], and has a boiling point of
73°C and a vapor pressure of 83 mm at 20°C [33].
 ^306] Garibyan, D. K.,  and S. A. Papoyan.  Study of the Blasto-
      mogenic Activity of Certain Chemical Substances Using a
      High-Speed Test Method.  Gig. Sanit., 8:74-76, 1977.

 "307] Garibyan, D. K.,  and S. A. Papoyan.  Use of Sebaceous Gland
      Reactions as a Test for Rapid Determination of Carcinogenic
      Activity of Chemicals.  Nekot. Itogi Izuch. Zagryazneniya
      Vnesh. Sredy Kanstserogen. Veschestoami; 112-115, 1972.


                                212

-------
                          Vinyl Bromide


Vinyl bromide  (bromoethylene, CAS No. 593-60-2) has not been
tested very much.  It was not found in Reference 5,  and from
CANCERLINE and TOXLINE only one author has conducted in vitro
tests on it.  In this test, 5. typhimurium strain TA 100 was
found to give a dose-response mutation frequency of 26 and 9
revertants per micromole per hour with and without the S9 liver
microsome fraction  [146].  It was also found that liver fractions
from human biopsies converted vinyl bromide to more mutagenic
compounds.  Another study by the same authors demonstrated that
vinyl bromide is activated by the liver homogenates in the same
manner as is vinyl chloride  [308].  Although there is not much
information on which to base any decision, vinyl bromide will
be considered a possible carcinogen for the first phase of this
project.

Production and Persistence

It is estimated that 4 x 103 kg/year of vinyl bromide is emitted
from stationary sources  [1].
 ;308] Barbin, A., et al.   Liver-Microsome-Mediated  Formation  of
      Alkylating Agents  from Vinyl  Bromide  and  Vinyl  Chloride.
      Biochem.  Biophys.  Res. Comm.,  67 (2) :596-603,  1975.
                                213

-------
                         Vinyl Chloride


Vinyl chloride (CAS No. 75-01-4) has been found to cause lung
tumors, mammary carcinomas and angiosarcomas in mice following
exposure by inhalation [309].   Similar exposure for rats produces
angiosarcomas of the liver and other organs, zymbal gland carci-
nomas, and nephroblastomas [309].   In view of the extreme rarity
of angiosarcoma of the liver in the general population, 16 cases
in vinyl chloride workers is evidence of a causal relationship.
It has also been found to be a mutagen of S. typhimurium (Ames
test  [97] and in enhancement of viral transformation (personal
communication with B. C.  Casto on 9 February 1978).

Production and Persistence

It is estimated that 1.4  x 108 kg is emitted per  [1].  The 1973
production of vinyl chloride was 2.4 x 109 g in the United States,
of which 97% was used for production of polyvinyl chloride [309].
A 1974 EPA estimate was 9 x 107 kg released to the atmosphere
[309].  Other estimates of production are 2.5 x 109 kg (1974)
[8]  and 2.5 x 109 kg, 1.9 x 109 kg and 2.6 x 109 kg in 1974,  1975,
and 1976 [32].  The demand for PVC is expected to increase at an
annual rate of 8-10% through 1981  [32].  In the atmosphere it
reacts with the HO radical with a 12-hour half-life  [8].  It has
a boiling point of -14°C  and a vapor pressure of 2,660 mm at 25°C
[33] .
 [309] IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 7, 1974.  pp. 291-305.
                               214

-------
                       Vinylidene Chloride


Vinylidene chloride  (1,1-dichloroethylene, CAS No. 75-35-4) has
been found to be mutagenic in the S.  typhimurium test  [97, 146,
310] and in a metabolizing in vitro  system with E. coli K12  [311],
It has also been reported to be carcinogenic  in rats and rabbits
[312], and in preliminary studies 200 ppm were carcinogenic to
rats and mice by inhalation  [313].   On reference concludes that
airborne emissions of vinylidene chloride are not likely to pose
a significant risk to the general population  [314].  Vinylidene
chloride has been placed on the probable carcinogen list for this
project.

Production and Persistence

It is estimated that 2.1 x 105 kg are emitted a year from  sta-
tionary sources, with 70% of this coming from the oxychlorination
of ethylene dichloride  [1].  Other  estimates of production and
release are production of 2.7 x 107  kg with 4.1 x 105  kg released
[7], production of 1.2 x 10s kg with 1.4-1.8 x 106 kg  emitted and
a 5-10% growth rate predicted  [314],  1.2 x 108 kg produced with
1.1  x 106 kg released  [6], 7.7 x 107 kg produced from  1973 to
1975 with a 7% growth predicted  [32], and 2.7 x 107 kg produced
in 1972  [8].  The 03 and HO reactions are estimated to give less
than a 1-day half-life  [6], while another reference cites  HO
half-life of 26 hours  [8].  Evaporation of 50% from a  1-ppm solu-
tion at 25°C will occur in 22 minutes  [33].   It has a  vapor pres-
sure of 617 mm at 25°C and a boiling point of 37°C  [6].
 [310]  IARC  Information  Bulletin  on  the  Survey  of  Chemicals Being
       Tested  for  Carcinogenicity.   International  Agency  for
       Research  on Cancer,  Lyon,  Bulletin  No. 5, July  1975.

 [311]  Greim,  H. G.,  et  al.   Mutagenicity  in  Vitro and Potential
       Carcinogenicity of  Chlorinated  Ethylenes as a Function  of
       Metabolic Oxirane Formation.  Biochem. Pharmacol.,  24:2013-
       2017, 1975.
 [312]  Food  Additives, Packaging  Material  for Use  During  Irradia-
       tion  of Pre-Packaged Foods.   Fed. Register, 33:4569, 1968.

 [313]  Caputo, A.,  et al.   Oncogenicity  of Vinyl Chloride at Low
       Concentrations in Rats and Rabbits.  IRCS,  2:1582,  1974.

 [314]  Hushon, J.,  and M.  Kornreich.   Air  Pollution Assessment of
       Vinylidene  Chloride.   National  Technical Information
       Service No.  PB 256  738,  1976.
                                215

-------
                             Xylene


Some literature suggests that xylenes are noncarcinogenic irri-
tants [315, 316].   Other literature indicates that all of the
xylenes cause neoplasms on mice after dermal application  [6].
This may refer to the same study where an increased number of
unspecified tumors were observed in the mouse upon dermal appli-
cation of mixed xylene after the use of croton oil or methane  [7]
The results of this study are considered equivocal [7] and would
at most suggest that xylenes are promoters.  The old xylene
carcinogen literature is negative after skin painting mice  [5],
and xylene is considered a noncarcinogen for this project.
[315]  Pound, A. W.  Induced Cell Proliferation and the Initiation
      of Skin Tumor Formation in Mice by Ultraviolet Light.
      Pathology, 2(4):269-275,  1970.

[316]  Listgarten, M. A., et al.   Ultrastructural Alterations in
      Hamster Cheek Pouch Epithelium in Response to a Carcinogen.
      Arch. Oral Biol., 8(2):145-165, 1963.
                               216

-------
                           APPENDIX B

         A REVIEW OF THE CARCINOGEN COFACTOR LITERATURE
INTRODUCTION

This appendix presents the state-of-the-art review of the carcino-
gen cofactor literature that was performed as part of the first
year's effort on this contract.  Primary emphasis is given to
industrial chemicals and the effects of cofactors on the carcino-
genic potential of these chemicals.

The information presented is derived from more than 2,300 litera-
ture citations  (most included abstracts) accessed from CANCERLINE,
TOXLINE, MEDLINE, CANCERPROJ, AND CHEMCON searched through the
National Library of Medicine and Systems Development Corporation.

Some of the keywords or word stems* utilized in the computer
search were carcinogen..., cocarcinogen..., and syncarcinogen....
Other words used in conjunction with carcinogen... included:
modifier(s), promoter(s), inhibitor(s), enhancer(s), synergy, and
synergism.  This review attempts to summarize some of the signi-
ficant findings reported in the multitude of literature found on
this subject.

BACKGROUND

Chemically induced carcinogenesis in man is rapidly becoming one
of the greatest concerns of society.  Statistical data on the
incidence of cancer in humans and laboratory testing on animals
have indicated that a wide variety of chemical compounds are
responsible at least in part for many of the various forms of
human cancer.  These substances traverse a number of interfaces
and enter or contact the human body through media such as air,
food, water, physical contact, and medication.  In addition these
substances can undergo various changes at each interface, within
the media of transport, or within the human receptor.  Noncarcino-
genic substances when metabolized by the body have been found to
produce carcinogenic byproducts.
*The word stems and all terms beginning with them  (indicated
 by ...) were searched.
                                217

-------
There are various theories on the mechanism of carcinogenesis;
the more generally accepted is that of a biphasic response of
initiation and promotion.  Promotion implies a latent period after
initiation of a target receptor.  This also implies that the
system or mechanism can be inactivated or inhibited.  In conjunc-
tion wi .,h this theory many carcinogenic and noncarcinogenic
compounds or their metabolites have been found to interact with
other chemicals or agents to enhance or inhibit carcinogenic
activity.  This modification can take place by preliminary,
simultaneous, or subsequent contact of each substance with the
target receptor.

Obviously a complete characterization of the interaction of chemi-
cal substances in human carcinogenesis is a monumental task
because chemicals that are carcinogenic or are cofactors of
potential carcinogens exist simultaneously in the various spheres
of our environment and may act to inhibit or enhance other carcin-
ogenic activity in varying degrees.  This review presents the
findings of various researchers in the area of carcinogenic co-
factors; it identifies each substance, its method of interaction,
the human organs it affects, and its sphere of transport and
entry into the human body.

Apparently the terminology in the area of carcinogenic cofactors
has not been standardized or widely accepted, and terms such as
cocarcinogen, syncarcinogen, promoter, and enhancer are sometimes
used interchangeably.  According to Hecker  [317] the divergent
use of terminology in carcinogenesis has created a great deal of
confusion in tumor etiology.  Hecker attempts to standardize
these terms as follows:

Solitary carcinogens:  first order carcinogenic risk factors.
     The most simple toxicologic process of manifestation of
     their carcinogenic effect is unifactorial exposure of the
     target tissue.

Syncarcinogenesis:  generation of neoplasia caused by multi-
     factorial exposure to the target tissue.  Exposure to a
     submanifestational dose of a solitary carcinogen  [i.e.,
     benzo(a)pyrene] may  induce a distinct inclination to cancer,
     while a subsequent exposure to either a solitary carcinogen
     or to a cocarcinogen may augment the irreversible effects
     caused by the initial exposure.  When exposure is to more
     than one solitary carcinogen, it is sometimes called
     pluricarcinogenesis.
 [317] Hecker, E.  Definitions and Terminology in Carcinogenesis
      Analyses and Proposals  (Meeting Abstract).  Third  Inter-
      national Symposium on Detection and Prevention of  Cancer,
      1976.  p. 67.


                                218

-------
Cocarc_inogenesis:  exposure to a submanif estational dose of the
     solitary carcinogen followed by exposure to a cocarcinogen
     which alone does not produce tumors or cancer.

Other terms frequently employed are:

Promoters:  agents that interact with membranes, stimulate and
     alter genetic expression, and  increase cell proliferation
     rate.  Promotion, unlike initiation, is reversible, and the
     promoting agents must be applied repeatedly before tumors
     are formed  [318].

Enhancement:  this term is 'often used to describe synergistic
     effects of chemical agents.  Usually when  the chemical agent
     tested increases the incidence of  cancer cells or decreases
     the response time of cancer manifestation  over that of the
     known carcinogen, it is said to enhance carcinogenic activity

Inhibitors:  agents that block or retard the carcinogenic activity
     of a known carcinogen.  Also called anticarcinogens.

Discussion of carcinogenic cofactors is presented by the basic
means of human exposure, that is, dietary cofactors, physical
agents and body materials, therapeutic  agents and treatments,
environmental cofactors, and industrial chemicals and pollutants.
Some carcinogenic cofactors exist in several spheres and can be
introduced to the body in various forms.  In addition, certain
cofactors have demonstrated both synergistic and inhibitory
activity.  These overlaps and contradictions are addressed in the
review.

DIETARY COFACTORS

Dietary cofactors are those agents  which are taken internally as
part of routine dietary intake, or  in some  form supplement the
diet, which if present or absent affect carcinogenic activity.
Included in this category are dietary related agents such as
cooking aerosols.

In laboratory studies on rats  [319] fed diets deficient in lipo-
tropes  (choline, methionine, folic  acid), amino acids, and niacin,
 [318] Yuspa,  S. H.,  et  al.   Cutaneous  Chemical  Carcinogenesis:
      Past, Present,  and  Future.   J.  Invest.  Dermatol.,  67(1):
      199-208,  1976.
 [319] Rogers, A.  E.   Reduction  of  n-Nitrosodiethylamine  Carcino-
      genesis in  Rats by  Lipotrope or  Amino  Acid  Supplementation
      of  a Marginally Deficient Diet.   Cancer Res.,  37(1):194-
      199, 1977.
                               219

-------
and high in fat, liver cancer induced by several carcinogens was
enhanced.   This is shown again for amino acids in another  study
[320].   The addition of beef fat to an adequate diet did not
enhance turner induction.  Methionine, contained in both the amino
acid and lipotrope supplement, was postulated to have inhibitory
effect .yhich has also been reported to be found in other studies.
The principal carcinogen used in this study was N-nitrosodiethyl-
amine.   The protein amino acid L-cysteine has been found to also
inhibit cigarette smoke induced cancer  [321], while other  amino
acids such as DL-ethionine have been demonstrated to accelerate
chemically induced carcinogenesis in animal tests  [322, 323] .
DL-tryptophan, another common dietary component, has been  tested
in several studies, all of which demonstrated promotion of
chemically induced carcinogenesis in animals  [324-326].  Another
study of dietary components was performed [327] which showed that
[320] Syrotuck, J. A., and B. S. Worthington.  Nutritional Effects
      on Syngeneic Tumor Immunity and Carcinogenesis in Mice,  I.
      Selected Essential Amino Acids  (Meeting Abstract).  Fed.
      Proc.,  36(3):1163, 1977.

[321] Leuchtenberger,  C.,  and R. Leuchtenberger.  Protection of
      Hamster Lung Cultures by L-Cysteine Against Carcinogenic
      Effects of Fresh Smoke from Tobacco or Marihauana Cigar-
      ettes  (Meeting Abstract).  J. Cell. Biol., 70(2/Part 2):
      44a, 1976.

[322] Takamiua, K.,  et al.  Effect of Phenobarbital and
      DL-Ethionine on 4-(Dimethylamino)azobenzene-Metabolizing
      Enzymes and Carcinogenesis.  Gann, 64 (4) : 363-372 , 1973.

[323] Ito, N.,  et al.   The Development of Carcinoma in Liver of
      Rats Treated with m-Toluylenediamine and the Synergistic
      and Antagonistic Effects with Other Chemicals.  Cancer Res.,
      29(5) :1137-1145, 1969.

[324] Radomski, J. L., et al.  Cocarcinogenic Interaction Between
      D,L-Tryptophan and 4-Aminobiphenyl or 2-Naphthylamine in
      Dogs.  J. Natl.  Cancer Inst. , 58 (6) :1831-1834, 1977.

[325] Ito, N.,  et al.   Effect of Various Carcinogenic and Non-
      carcinogenic Substances on Development of Bladder Tumors
      in Rats Induced by n-Butyl-N-(4-hydroxybutyl)nitrosoamine.
      Gann,  65 (2) :123-130, 1974.

[326] Matsushima, M.  The Role of the Promoter L-Tryptophan on
      Tumorigenesis in the Urinary Bladder.  2.  Urinary Bladder
      Carcinogenicity of FANFT  (Initiating Factor) and L-Tryptophan
      (Promoting Factor) in Mice.  Jpn. J. Urol., 68(8) :731-736,
      1977.

[327] Rogers, A. E., and P. M. Newberne.  Dietary Effects on
      Chemical Carcinogenesis in. Animal Models for Colon and
      Liver  Tumors.   Cancer Res.,  35(ll/Part 2):3427-3431, 1975.
                                220

-------
colon tumor induction is increased by increased dietary fat in-
take or dietary deficiency of vitamin A.  The enhancing effect
was augmented by lipotrope deficiency.  A survey of  8,278
Norwegian men resulted in findings which suggest that vitamin A
active compounds inhibit pulmonary carcinogenesis in man  [328].

Vitamin A in conjunction with Fluorouracil has been  shown to
inhibit 7,12-dimethylbenzanthracene  (DMBA) induced skin tumors
in rabbits  [329] .  Vitamin B2 deficiency and hepatic injury
resulting from inadequate food  intake have been postulated to
promote liver cancer  [330].  However, nicotinamide,  a B vitamin,
has been shown in animal tests  to promote the development of
kidney neoplasms and  increase the incidence of pancreatic tumors.
It was also suggested that it may offer some protection against
the acute effects of  liver cancer but not against tumor
induction  [331] .

Studies have shown that synthetic inducers of increased micro-
somal mixed function oxidase activity may inhibit the neoplastic
effect of chemical carcinogens  [332].  An increasing number of
these substances are being found in natural products.  Cruciferous
vegetables including brussels sprouts, cabbage, and cauliflower
have been found to contain indole-3-acetonitrile, indole-3-carbinol,
and 3,3'-diindolymethane which  have been identified as inducers
of oxidase activity, or potential carcinogenic inhibitors.

Another category of dietary inhibitors comprises the antioxidants.
Several of these compounds have been found to inhibit the carcino-
genic effects of a variety of chemical carcinogens in animal
tests.   Considerable work has been done with butylated hydroxy-
anisole (BHA) and butylated hydroxytoluene (BHT), phenolic
 [328] Bjelke, E.  Dietary Vitamin A and Human Lung Cancer.
      Int. J. Cancer, 15 (4) :561-565,  1975.
 [329] Prutkin, L.  Inhibition of Tumorigenesis by Topical
      Application of Low Doses of Vitamin A Acid and Fluorouracil.
      Experientia, 31(4) :494, 1975.

 [330] Sugimura, T.  Carcinogens in Foods and Food Products.
      Proceedings of the Eleventh Canadian Cancer Research
      Conference, Natl. Cancer Inst.  Canada, Toronto, Ontario,
      6-8 May 1976, 1976.
 [331] Schoental, R.  The Role of Nicotinamide and of Certain
      Other Modifying Factors in Diethylnitrosamine Carcinogenesis
      Fusaria Mycotoxins and "Spontaneous" Tumors in Animals and
      Man.  Cancer  (Suppl.), 40 (4) :1835-1840, 1977.

 [332] Wattenberg, L. W. et  al.  Dietary Constituents Altering
      the Response to Chemical Carcinogens.  Fed. Proc.,
      35:1327-1331, 1976.


                                221

-------
antioxidants extensively used as food additives.  In studies
[333] where BHA and BHT were added to the diet of mice with
benzo(a)pyrene [B(a)P]  it was found that either antioxidant in-
hibited carcinogenesis.   Other antioxidants having carcinogenic
inhibiting capabilities include dimethylhydrazine, tetraethyl-
thiurar  disulfide, ethoxyquin, disulfiram, dimethyldithiocarbamate,
6-ethoxy-l,2-dihydro-2,2,4-trimethylquinoline  (commerical animal
food additive),  cysteamine, benzyl isothiocyanate and benzyl
thiocyanate (naturally  occurring antioxidants), sodium selenide,
and a-tocophenol  [330,  332, 333].  Large quantities of salt may
enhance the action of gastrocarcinogens such as N-methyl-N'-nitro-
N-nitrosoguanidine (MNNG)  [330].

The artificial sweeteners saccharin and cyclamates have been
shown to act as cocarcinogens with subcarcinogenic doses of N-methyl-
N-nitrosourea, a strong bladder carcinogen, when tested on rats
[334, 335].  Another study on mice, however, concluded that
these artificial sweeteners had no carcinogenic or cocarcinogenic
activity under the experimental conditions  [336],

Coffee has been shown to contain constituents of which some have
been shown to promote and others to inhibit carcinogenesis.  Caf-
feine has been tested on mice as a post treatment to exposure to
4-nitroquinoline-l-oxide (4NQO), a known carcinogen, and showed
inhibitory properties [337] .   In contrast chlorogenic acid (13% of
the soluble constituent of coffee)  has been shown to be a very
powerful catalyst for N-nitrosoamine formation in the digestive
[333]  Wattenberg, L.  W.   Inhibition of Chemical Carcinogenesis
      by Antioxidants and Some Additional Compounds.  In:
      Fundamentals in Cancer Prevention, Proceedings of the 6th
      International Symposium of The Princess Takamatsu Cancer
      Research Fund,  Tokyo, Japan, 1976.  pp. 153-166.

[334]  Chowaniec, J.,  et al.  Histology of Tumour Formation in the
      Bladder of Rats Receiving Dietary Saccharin and a Single
      Dose of n-Methyl n-Nitrosourea (Meeting Abstract).   B. J.
      Cancer, 29 (1) :93,  1974.

[335]  Hicks, R. M., and J. Chowaniec.  The Importance of Synergy
      Between Weak Carcinogens in the Induction of Bladder Cancer
      in Experimental Animals and Humans.  Cancer Res., 37(8,
      Part 2):2943-2949, 1977.

[336]  Roe, F. J., et  al.  Feeding Studies on Sodium Cyclamate,
      Saccharin and Sucrose for Carcinogenic and Tumour-Promoting
      Activity.  Food Cosmet. Toxicol., 8(2):135-145, 1970.

[337]  Nomura, T.  Inhibitory Effect of Caffeine on Chemical
      Carcinogenesis  in Mice  (Meeting Abstract).  Proc. Am. Assoc
      Cancer Res., 18:244, 1977.
                               222

-------
tract [338].  Tests conducted on mice indicate that neutral ste-
rols (cholesterol, caprostanol, and caprostanone) are moderately
inhibitory on B(a)P carcinogenesis  [339].  However, other
researchers have found cholesterol to promote carcinogenesis
which was previously inhibited by phospholipids  [340].

Nitrosoamines, known to have carcinogenic activity, have been
shown to act synergistically with B(a)P, resulting in a higher
incidence of lung and stomach tumors in animals  than if each
agent were administered separately  [341].  Nitrosoamines may not
enter the human body as such but can be formed through metabolic
processes and altered by other agents.  For instance, nitrites
can react with secondary amines to yield nitrosoamines, and
substances such as gallic acid and 4-methylcatechol  (in coffee)
enhance formation of nitrosoamines, whereas ascorbic acid
depresses formation of nitrosoamines  [330].  Dietary sodium
sulfate has been shown to enhance azo dye carcinogenesis  [342].

Many major constituents of essential oils, flavors, and spices
are also considered tumor promoting and carcinogenic. The major
constituent of orange oil, D-limonene, is a skin tumor promoting
agent in mice, while turpentine oil and eucalyptus oil contain
the cocarcinogens L-pinene and phellandrene.  Other essential
oils with lower terpene levels have less tumor promoting
 [338] Challis,  B.  C.,  and  C.  D.  Bartlett.   Possible  Cocarcinogenic
      Effects of  Coffee  Constitutents.   Nature  (Lond.),  254(5500):
      532-533,  1975.
 [339] Watanabe, K.,  et al.   Effect  of  Bile  Acids  and Neutral
      Sterols on  Benzo(a)pyrene-Induced  Tumorigenesis  in Skin  of
      Mice:  Brief Communication.   J.  Natl.  Cancer Inst.,  60(6):
      1501-1503,  1978.
 [340] Altman, R.  F.,  et  al.   Phospholipids  Retard and  Cholesterol
      Promotes  the Formation of  Tumours  Induced by Carcinogenic
      Hydrocarbons.   Z.  Naturforsch.  (B) ,  23 (9) :1277-1279,  1968.

 [341] Bingham,  E.,  et al.  Multiple Factors in  Carcinogenesis.
      Ann. N.Y. Acad.  Sci.,  271:14-21,  1976.

 [342] Blunck, J.  M.,  and C.  E. Crowther.   Enhancement  of Azo  Dye
      Carcinogenesis  by  Dietary  Sodium Sulphate.  Eur.  J. Cancer,
      11(1):23-31,  1975.
                               223

-------
activity [343].   Citrus oils and croton oil have been found to be
cocarcinogenic [344,  345].

Studies indicating that certain cooking oils possess cocarcino-
genic activity have been reported since 1964.  Triolein, a major
constituent of cottonseed oil and sesame oil, was tested on mice
and was found to be cocarcinogenic [346, 347].

Tests with butter oil and sunflower oil have demonstrated that,
when overheated, these oils possess carcinogenic and cocarcino-
genic properties [348].  Studies using a mutant safflower oil
rich in oleic acid indicate that polyunsaturated fats act as
cocarcinogens [349].   Cyclopropenoid fatty acids (CPFA)  (e.g.,
sterculic acid and malvalic acid) occur in certain foodstuffs such
as cottonseed oil, kapok oil, and flour and have been demonstrated
to act as powerful tumor promoters or cocarcinogens for  aflatoxin
[343]  Homburger, F.,  and E.  Boger.   The Carcinogenicity of
      Essential Oils,  Flavors,  and Spices:  A Review.  Cancer
      Res.,  28(11) :2372-2374, 1968.

[344]  Salaman,  M.  H.,  and F. J.  Roe.  Cocarcinogenesis.  Br.  Med.
      Bull.,  20(2):139-144,  1964.

[345]  Schramm,  R.,  and W. Gibel.  Carcinogenic and Cocarcinogenic
      Plant Products,  II.  Carcinogenic Substances Synthesized by
      Pteridophyta (Filicinae)  and Spermatophyta (Cyadineae,
      Dicotyledoneae,  Monocotyledoneae).   Arch. Geschwulstforsch.,
      33(2):169-188,  1969.

[346]  Zschiesche,  W.,  and G. Bruns.   Carcinogenesis of 7-Keto-
      cholesterol.   Oncology, 18(4) : 289-299 , 1964.

[347]  Bryson,  G.,  and F. Bischoff.   Triolein as a Cocarcinogen.
      Fed.  Proc.,  23(2, Pt.  1):106,  1964.

[348]  Dzagnidze, L.  I., and P.  N.  Krasniyanskaya.  A Study of
      Possible Carcinogenic and Cocarcinogeni Properties of
      Overheated Oils.  Soobshch.  Akad. Nauk. Gruz. SSR, 67(1):
      229-231,  1972.

[349]  Dayton,  S.,  et al.  Effect of  High-Oleic and High-Linoleic
      Safflower Oils on Mammary Tumors Induced in Rates by 7,12-
      Dimethylbenz(alpha)anthracene.  J.  Nutr., 107 ( 8) :1353-1360 -
      August 1977.


                                224

-------
induced liver cancer in trout  [350-352].  Because it has been
suggested that the high incidence of colon cancer in man is due
to lack of dietary fiber, studies were conducted on rats using
wheat bran, pectin, alfalfa, and carrageenin.  Fifteen percent
dietary carrageenin promoted colon tumors, and the modifying
effect of dietary fibers depended on the type of fiber used  [353]

A study of furfural on the respiratory tract of hamsters suggests
it is a cocarcinogenic agent with B(a)P  [354].  Furfural can be
found in cigarette smoke but also in foodstuffs including bread,
coffee, processed fruits and juices, and alcoholic beverages.
This may be supported by a study which showed that extracts from
dried plums showed cocarcinogenic activity  [355].

Although alcohol is not part of what is considered a normal diet,
alcoholic beverages are consumed by many people.  It is estimated
that alcohol plays an etiological role in greater than 50% of the
oropharyngeal cancers in the United States  [356].
 [350] Sinnhuber,  R.,  O.,  et  al.  Metabolism and Cocarcinogenicity
      of Cyclopropenes.   Oregon  State Higher Educ. Sys., School of
      Agriculture,  Food  Science  and Technology, Corvallis, Oregon.
 [351] Lee, D. J., et  al.   Synergism Between Cyclopropenoid Fatty
      Acids and Chemical  Carcinogens in  Rainbow Trout  (Salmo
      Gairdneri) .   Cancer Res.,  28 (11) :2312-2318,  1968.

 [352] Petering, H.  D.  Diet,  Nutrition,  and Cancer.  Adv. Exp.
      Med. Biol., 91:207-228,  1977.
 [353] Raikow, R.  B.   Effects  of  Carcinogens or Suspected Carcino-
      gens on Viral Luekemogenesis in C57BL/10, SJL/J  Mice and
      Their Fl Hybrid (Meeting Abstract).  Proc.  Am. Assoc.
      Cancer Res.,  19:23, 1978.
 [354] Rick, E. W.   Furfural:   Exogenous  Precursor of Certain
      Urinary Furans  and  Possible  Toxicologic Agent  in Humans.
      Clin. Chem. ,  18 (12) :1550-1551, 1972.
 [355] Ruchkovskii,  B.  S., et  al.   Carcinogenic and Cocarcinogenic
      Action of Dried Fruit  Extract.  Vopr. Onkol.,  20(4):58-61,
      1974.
 [356] Rothman, K. J.   The Effect of Alcohol Consumption on Risk
      of Cancer of  the Head  and  Neck.   (Head and  Neck  Cancer,
      State-of-the-Art Conference, St. Louis, MO., February  16-18,
      1976.)  Laryngoscope,  88(1,  Part 2,  Suppl.  8):51-55, 1978.
                                225

-------
An investigation of the incidence of oral cancer in women who
smoke and drink indicates that alcohol is a cocarcinogen with
cigarette smoke [357].   This is also suggested in another study
[358].  Another study performed on rats suggests a synergism
between inhaled vinyl chloride and ingested alcohol in
tumorigenesis [359].

Investigations of the effect of masticatory substances such as
chewing tobacco and betel nuts have indicated that in conjunction
with tobacco smoke these substances may be cocarcinogens  [360,
361] .

PHYSICAL AGENTS AND BODY MATERIALS

Physical agents which act as carcinogenic cofactors are generally
those which act upon or contact the human body but usually are
not chemical in nature, such as forces or forms of energy (x-rays)
Body materials are those which relate to body chemistry or body
functions.

The tissues in the human oral cavity are generally exposed to
repeated low doses of x-rays from diagnostic medical and dental
radiology.  Studies have been performed on hamster cells and
hamster cheek pounch where repeated low doses of x-rays have
exhibited carcinogenic or tumor promoting activity with repeated
low doses of a known carcinogen  (DMBA) or where x-ray treatment
 [357] Bross, I. D., and J. Coombs.  Early Onset of Oral Cancer
      Among Women Who Smoke and Drink.  Proc. Am. Assoc. Cancer
      Res., 17:1, 1976.

 [358] Gibel, W., and G. Wittig.  On the Experimental Induction of
      Carcinoma of the Esophagus.  Dtsch. Gesundheitsw., 19(14):
      635-637,  1964.

 [359] Radike, M. J., et al.  Effect of Ethanol and Vinyl Chloride
      on the Induction of Liver Tumors:  Preliminary Report.
      Environ.  Health Perspect., 21:153-155, 1977.

 [360] Jayant, K.  Statistical Appraisal of the Association of
      Smoking and Chewing Habits to Oral and Pharyngeal Cancers.
      Indian J. Cancer, 14 (4) :293-299, 1977.

 [361] Ranadive, K. J., et al.  Experimental Studies on Betel Nut
      and Tobacco Carcinogenicity.  Int. J. Cancer, 17 (4) :469-476,
     15 April 1976.

                               226

-------
preceded administration of the carcinogenic agent  [362, 363].
The cofactor effect of ultraviolet  (UV) light is not quite as
well defined.  A study of the effect of UV light exposure to
hamster cells followed by B(a)P or N-acetoxyfluorenyl-acetamide
resulted in neither an additive nor synergistic enhancement
observed with either chemical agent alone  [363].  However, another
study showed significant enhancement by UV light on DMBA initiated
skin carcinogenesis  [329] .  The explanation appears to be in the
sequence of exposure.  An additional study on nonhuman primates
demonstrated that DMBA was oncogenic when applied to the skin in
combination with UV light  [364].

Removal of the gall bladder  (cholecystectomy) has been suggested
in several studies to have a cocarcinogenic effect in cancer of
the colon.  A detailed investigation of 760 cases of large bowel
cancer revealed a strong associate between cholecystectomy and
ascending colon cancer  [365].

An experimental study on mice was initiated when another group of
researchers showed clinical  findings that 10% of patients with
carcinoma of the large bowel had previous cholecystectomies.  This
cocarcinogenic effect was verified  in  the animal tests with the
carcinogen 1,2-dimethylhydrazine  (DMH).  The cocarcinogenic effect
of cholecystectomy was assumed  to be due to an  increased produc-
tion of secondary bile salts by the colonic bacteria and the lack
of resorptive function of the gall bladder for  some carcinogenic
material  [366] .  Bile salts  in  the  colon introduced by surgical
means have been demonstrated in other  animal studies to enhance
 [362]  Hecht,  S.  S.,  et al.   Chemical Studies  on  Tobacco  Smoking
       Determination  of Hydroxybenzyl Alcohols and  Hydroxyphenyl
       Ethanols  in  Tobacco and Tobacco Smoke.   J. Anal. Toxicol.,
       2(2):56-59,  1978.
 [363]  DiPaolo,  J.  A.,  and P.  J.  Donovan.   In  Vitro Morphologic
       Transformation of Syrian Hamster Cells  by  U.V--Irradiation
       is  Enhanced  by X-Irradiation and Unaffected  by Chemical
       Carcinogens.   Int.  J.  Radiat.  Biol.,  30(l):41-53,  July 1976

 [364]  Palotay,  J.  L.,  et al.   Carcinogen-Induced Cutaneous
       Neoplasms in Nonhuman  Primates.  J.  Natl.  Cancer Inst.,
       57 (6) :1269-1274, 1976.
 [365]  Lohsoonthron,  P.  The  Epidemiologic  Study  of Subsite  Large
       Bowel  Cancer.   Diss. Abstr.  Int. (B) ,  36 (9) :4399-B,  1976.

 [366]  Werner,  B.,  et al.   Cholecystectomy  and Carcinoma  of  the
       Colon,  An Experimental Study.   Z. Krebsforsch.,  88 (3):223-
       230,  1977.

                                 227

-------
the carcinogenic effect of substances such as azoxymethane  [367,
368].  Other substances present in the large bowel of man have
been tested in animal models for their cofactor activity-  Bile
acids such as cholic acid, chenodroxycholic acid, and lithocholic
acid were tested on rats with the carcinogen MNNG and indicated
that pr Lmary bile acids modified to secondary bile acids by
intestinal bacteria exert a strong promoting effect in colon
cancer [369] .  These same bile acids along with neutral sterols
acted as inhibitory agents to B(a)P induced skin tumors on mice
[339].   Fecal samples of patients with colon cancer have shown
large amounts of bile acids, cholesterol metabolites, high fecal
bacterial 7-alpha-dehydroxylase and cholesterol dehydrogenase
activity [370].  The chemical fluid, adenosine 3',5'-cyclic
monophosphate, is found in all living cells and is essential for
muscular action.  This substance has been found to enhance skin
carcinogenesis by 7,12-dimethylbenzanthracene [371].

Previous findings that trauma is a potential cocarcinogen was
supported by two cases of women who developed breast cancer in
old thoractomy scars.  In each case the combination of scar tissue
and surgical trauma seemed significant in the development of
cancer [372].  It has also been reported that chronic inflamma-
tion can be a cocarcinogenic factor in the formation of bone
cancer [373] .
 [367] Williamson, R. C., et al.  The Effect of Pancreatobiliary
      Diversion on Testical Carcinogenesis  (Meeting Abstract).
      Br. J. Surg., 64(11):837, 1977.

 [368] Reddy, B. S.  Role of Bile Metabolites in Colon Carcino-
      genesis.  Cancer  (Suppl.), 36:2401-2406, 1975.

 [369] Reddy, B. S., et al.  Promoting Effect of Bile Acids on
      Colon Carcinogenesis in Germfree and Conventional Rats
      (Meeting Abstract).  Proc. Am. Assoc. Cancer Res., 18:119,
      1977.

 [370] Wynder, E. L.  Metabolic Epidemiology of Colon Cancer.
      Amer. Health Foundation, Inc., New York, New York.

 [371] Curtis, G. L., et al.  Enhancement of 7,12-Dimethyl-
      benzanthracene Skin Carcinogenesis by Adenosine, 3',5'-
      Cyclic Monophosphate.  Cancer Res., 34 (9) :2192-2195, 1974.

 [372] Freund, H., et al.  Breast Cancer Arising in Thoracotomy
      Scars  (Letter to Editor).  Lancet, 1(7950):97, 1976.

 [373] Glaser, A.  Pathologic and Clinical Aspects of Bone Tumors,
      Zentralbl. Chir., 101(6):321-329, 1976.
                               228

-------
In a survey of lung cancer patients who smoked, chronic bron-
chitis was shown to be cocarcinogenic with cigarette smoke  [374].
In a study of the mechanism of action of polycyclic aromatic
hydrocarbon carcinogens it was suggested that antibodies to the
carcinogen may enhance the tumorigenicity of the carcinogen  [375].
The effects of chronic mechanical  irritation of the gastric
mucous membrane on stomach carcinogenesis was investigated.  It
was concluded that foreign bodies  had promotive effects in glan-
dular stomach carcinogenesis by MNNG, possibly by prolonging
retention of the carcinogen and in turn the exposure to the gas-
tric mucous membrane  [376].

Tests conducted in Russia on the effect of magnetic fields on
rats concluded that magnetic fields enhanced tumor growth initi-
ated by B(a)P or polyvinyl chloride  (PVC)  [377].  It has also
been reported that rotary motion causes stress which stimulates
the functioning of the pituitary glad or adrenal cortex, thus
promoting tumor development  [378].

THERAPEUTIC AGENTS AND TREATMENTS

Tests have shown that several  therapeutic agents exhibit carcino-
genic cofactor activity.   It is most ironic that certain cancer
therapy drugs have been found  to be carcinogenic as well as
therapeutic in experimental systems.  An example of this is
actinomycin D which can act as a cancer therapy drug,  antccarcino-
gen, and carcinogen  [379].  Other  cancer therapy drugs also act
as cocarcinogens and  augment the tumorigenicity of chemical
carcinogens.  Clinical studies suggesting an increased incidence
of malignant neoplasms in  patients with Hodgkin's disease treated
 [374]  Lung  Cancer  and  Chronic  Bronchitis.   Med.  M.  Aust.,  51(24):
       926-927,  1964.
 [375]  Stenback,  F.,  and  G.  Curtis.   Mechanism of Action  of Poly-
       cyclic  Hydrocarbon Carcinogens:   Immunological  Aspects
       (Meeting  Abstract).   Scand.  J.  Immunol.,  6(11):1196,  1977.

 [376]  Fukushima, S.,  et  al.  Effects of Foreign Bodies on  Gastric
       Carcinogenesis  in  Rats Treated with n-Methyl-n'-nitro-n-
       nitrosoguanidine (MNNG).   (Proc.  Jpn.  Cancer  Assoc.,  33rd
       Annual  Meeting,  October  1974.)   Gann,  67,  1975.

 [377]  Kogan,  A.  K.  H., and  V.  I.  Kulitskaia.   The Effect of a
       Stationary Magnetic Field on Induced Carcinogenesis.   Patol,
       Fiziol.   Eksp.  Ter.,  (2):63-68,  1977.
 [378]  Suzuki, S.   Effect of Rotary Motion on Carcinogenesis.
       J.  Nagoya City  Univ.  Med. Assoc., 19(4):1517-1558, 1969.

 [379]  Harris, C. C.   The Carcinogenicity of Anticancer Drugs:  A
       Hazard  in Man.   Cancer,  37 (2) :1014-1023,  1976.
                                 229

-------
intensively with radiation and chemotherapy prompted testing on
animals.   Test results indicated that procarbazine and ionizing
radiation have a synergistic carcinogenic action  [380].

Other tests with urethan, an antileukemic drug, demonstrated its
behavic  as both a carcinogenic and cocarcinogenic agent  [344,
381].  Melphalan (L-phenylalanine mustard), a cytostatic drug
used in the treatment of breast cancer, markedly enhanced mammary
tumor formation in mice  [382].  Results of tests on allopurinol,
used in the treatment of gout and human neoplasia, demonstrate its
enhancement potential of bladder cancer in rats induced by N[4-
(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) [383].  Data from
several cancer centers indicate that immunosuppressive drugs  (in
transplant recipients) may also act as cocarcinogens with UV
light in the induction of skin cancer  [384] .  •

Griseofulvin, an antifungal antibiotic, acted as a cocarcinogen
with skin applications of 3-methylcholanthrene in mice but not
with B(a)P [385].   In a similar study griseofulvin was found to
inhibit skin tumors promoted by croton oil and induced by B(a)P
but lacked promoting activity by itself [386].

Cignolin, used in the treatment of psoriasis, was tested on mouse
skin pretreated with a carcinogenic agent (DMBA or tar).   The
 [380] Arseneau, J. C., et al.  Synergistic Carcinogenic Effect of
      Procarbazine and Ionizing Radiation in CDF Mice.  Proc. Am.
      Assoc. Cancer Res., 16:120, 1975.

 [381] Kosir, A.  Contribution of Carcinogenesis.  Acta Med.
      lugosl., 16(2):172-180, 1962.

 [382] Medina, D.  Enhancement of Mammary Tumor Formation in Mice
      by a Cytostatic Drug, Melphalan.  Cancer Res.,  38(1):317-
      319, 1977.

 [383] Want, C. Y., and S. Hayashide.  Enchancement of N-[ 4-( 5-nitro-
      2-furyl)-2-thiazolyl]formamide  (FANFT Carcinogenicity for
      Rat Urinary Bladder by Allopurinol.  Proc. Am. Assoc. Cancer
      Res., 17:149, 1976.

 [384] Maize, J. C.  Skin Cancer in Immunosuppressed Patients.
      JAMA, 237(17):1857-1858, 1977.

 [385] IARC Monographs:  Evaluation of the Carcinogenic Risk of
      Chemicals to Man, Volume 10, 1976.  pp. 153-161.

 [386] Vesselinovitch, S. D., and N. Mihailovich.  The Inhibitory
      Effect of Griseofulvin on the "Promotion" of Skin
      Carcinogenesis.  Cancer Res., 28 (12) :2463-2465, 1968.


                               230

-------
aPPlication of cignolin promoted the formation of skin tumors in
more than one-third of the animals tested  [387] .

Animal studies employing the sedative phenobarbital have demon-
strated that it can act as a carcinogenic  inhibitor or enhancing
agent.  Phenobarbital given together v/ith  diethylnitrosoamine
(DENA) reduced the severity of  liver carcinogenesis but when
administered after DENA it enhanced carcinogenesis  [388].  Pheno-
barbital also enhanced azo-dye  induced  liver carcinogenesis in
rats  [389] while inhibiting 4-(dimethylamino)azobenzene induced
carcinogenesis  [322].

Steroidal anti-inflammatory agents have been tested on mouse skin
and have been found to inhibit  skin carcinogenesis.  Dexamethasone
and fluocinolone were the most  effective inhibitors while estra-
diol, estrone, estriol, testosterone and progesterone were found
to act as inhibitors but to a lesser degress  [390, 391].  Steroidal
compounds have also been tested for their  cofactor activity in
other human applications.

Estradiol dipropionate, an estrogenic compounds, was tested on
rabbits with the carcinogen methylcholanthrene, and the results
suggest that estrogen may promote uterine  cancer  [392].  Similar
studies with estrogenic compounds and prolactin suggest a
 [387] Langbein, W.  Contribution  to  the  Cocancerogenic Effect of
      Cignolin  in Animals.   Radiobiol. Radiother.  (Berl.),
      13(2):233-240,  1972.
 [388] Weisburger, J.  H.,  et  al.   Modification  of Diethylnitroso-
      amine Liver Carcinogenesis  with Phenobarbital but Not with
      Immunosuppression.   J.  Natl. Cancer  Inst., 54(5):1185-1188,
      1975.
 [389] Kitagawa, T., and  H. Sugano.   Enhancement of Azo-Dye
      Hepatocarcinogenesis with Dietary  Phenobarbital  in  Rats.
      Gann, 68 (2) :255-256, 1977.
 [390] Van  Duuren, B.  L.   Tumor-Promoting and Cocarcinogenic Agents
      in Chemical Carcinogenesis.  In:   Chemical Carcinogens,
      Searle, C. E.,  ed.,  American Chemical Society Monograph
      1973, American  Chemical Society, Washington, D.C.,  1976.
      pp.  24-51.
 [391] Slaga, T. J., et al.   Mechanism of Action of Steroidal
      Anti-Inflammatory  Agents that  Inhibit Skin Carcinogenesis.
      Proc. Am. Assoc. Cancer Res.,  16:37,  1975.

 [392] Kawaguchi, K.   Studies on Experimental  Induction of
      Endometrial Carcinoma  in Rabbits,  Especially Related  to
      Their Carcinogenesis (Meeting  Abstract).  Acta  Obstet.
      Gynaecol. Jpn., 21(1):68, 1976.


                                231

-------
synergistic effect on formation of rat mammary tumors  [393-395]
and a synergistic effect on cervical carcinomas induced by 3-
methylcholanthrene (MCA) [396].  However, other researchers,
although recognizing that estrone and estradiol are linked to
carcinogenicity and cocarcinogenicity, feel that estrogen levels
in ora.1 contraceptives are too low to affect genital carcinoma and
do not elevate the risk of breast cancer  [397].  Another study
performed on rats gives evidence to support the concept that
sustained elevation of estriol in body fluids inhibits breast
carcinogenesis [398].

Enovid, a mammary growth promoting agent, is made up of 98.5%
norethynodrel and 1.5% mestranol.  Tests conducted with this
substance on rats sugget that it may inhibit the carcinogenic
induction of mammary tumors but may enhance the growth of tumors
already present [399] .  Based on medical histories of two women
it was suggested that liver cancer may be caused by a synergistic
effect of estrogen and progesterone [400].
 [393] Muhlbock, 0., and L. M. Boot.  The Mode of Action of Ovarian
      Hormones in the Induction of Mammary Cancer in Mice.  Bio-
      chem. Pharmacol., 16(4):627-630,  1967.

 [394] Warren, S., and 0. Gates.  Radiation Carcinogenesis,
      Progress Report IV, 15 March 1976 - 15 May 1977.  Available
      through National Technical Information Service, Springfield,
      VA, as COO-3017-31, EY-76-S-02-3017, 1977.  15 pp.

 [395] Lee, C., et al.  In Vitro Interaction of Estrogen and
      Prolactin on Hormone-Dependent Rat Mammary Tumors.
      Proc. Soc. Exp. Biol.  Med., 148(1) :224-226, 1975.

 [396] Forsberg, J. G., and L. S. Breistein.  A Synergistic Effect
      of Oestradiol and Prolactin Influencing the Incidence of
      3-Methylcholanthrene Induced Cervical Carcinomas  in Mice.
      Acta Pathol. Microbiol. Scand  (A), 84(5) :384-390, 1976.

 [397] Vorherr, H.  Contraception Postabortion and Postpartum,
      Advantages and Disadvantages of Hormonal Contraceptive with
      Particular Reference to the Relationship Between  Female Sex
      Hormones and Thromboembolism and Carcinoma of  the Breast
      and Genitals.  Gynaekol.  Rundsch., 15(1):48-73,  1975.

 [398] Lemon, H. M.  Estriol and Prevention of Mammary  Carcinoma.
      Cancer Detec. Prevent., 1(2):263-281, 1976.

 [399] Welsch, C. W.  Effects of a Norethynodrel-Mestranol
      Combination  (ENOVID) on Development and Growth of Carcino-
      gen-Induced Mammary Tumors in Female Rats.  Cancer,
      23(3):601-607, 1969.

 [400] Chevrel, B.  Role of Steroid Hormones in the Development
      of Malignant Tumors (Letter to Editor).  Nouv. Presse. Med.,
      5(17):1145, 1976.


                                232

-------
Several adrenergic agents have been tested on animals for their
cofactor effect.  Noradrenaline and atropin were found to enhance
liver cancer while isoprenalin inhibited it  [401].

ENVIRONMENTAL COFACTORS

Cigarette smoke is an important environmental constituent contain-
ing many components which exhibit carcinogenic cofactor activity.
A series of 21 tobacco smoke components and related compounds were
tested for cocarcinogenic activity on mouse skin with B(a)P as the
active carcinogen.  The results of the tests are summarized in
Table B-l.

       TABLE B-l.  COCARCINOGENESIS EXPERIMENTS:  SUMMARY


  	Cocarcinogenic activity	      Inhibitory activity
                      Weak or
     Potent	moderate	  Partial	Complete

  Catechol      Benzo(ghi)perylene   Phenol        Esculin

  Pyrogallol    Lauryl alcohol       Eugenol       Quercetin

  Decane        Tetradecane          Resorcinol    Squalene

  Undecane                           Hexadecane    Oleic acid

  Pyrene                             Hydroquinone

  B[e]P                              Limonene

  Fluoranthene
Six of the  21 compounds were  also  tested  as  tumor promoters in
two-stage carcinogenesis.  No direct  correlation was found
between  tumor promoting activity and  cocarcinogenic activity.
The cocarcinogens pyrogallol  and catechol did  not show  tumor
promoting activity, while  decane,  tetradecane,  anthralin, and
phorbol  myristate acetate  showed both types  of activity [212].
In addition, tumor promoting  or cocarcinogenic activity has been
 [401] Gurkalo,  B.  L.,  and  M.  A.  Zabezhinsky.   Modification  of
      Chemical  Carcinogenesis with Adrenergic  Compounds.  Vestn
      Akad,  Med. Nauk  SSSR,  (2):38-42,  1978.
                                233

-------
attributed to other compounds isolated from cigarette smoke
including alkyl naphthalenes and nitrosoamines [402, 403].

These findings are important because many of the above substances
are alsr contacted by man through either industrial pollution or
natural sources (food, etc.).

Another study was undertaken to examine the effect of nicotine on
the carcinogenic activity of cigarette smoke condensate on mouse
skin.  Early in the experiment the largest administered dose of
nicotine appeared to inhibit tumor formation.  However, at 37
weeks the results demonstrated that low to moderate concentra-
tions of nicotine act as important cocarcinogenic stimuli  [404] .
Another important potential environmental factor is human viruses.
A study of nasopharyngeal carcinoma in Southeast Asia has
suggested an undefined cocarcinogenic role for Epstein-Barr virus
[405].   Cocarcinogenic activity of viruses was also suggested in
a study of hamster tumors.  Primary tumors grafted to new animals
showed malignant characteristics not present in the original
tumors.  The malignant potential of the cells could be correlated
with the presence of viral particles acting as cocarcinogens  [406]
Further studies have been conducted to specifically investigate
the cocarcinogenic activity of viruses.  On one test human embryo
lung cells were infected with oncornavirus LPV and then treated
with the carcinogen MNNG.  It was concluded that a synergistic
effect existed between MNNG and the oncogenic virus  [407].
Another significant finding in the area of cocarcinogenic viruses
 [402] Schmeltz, I., et al.  Formation and Determination of
      Naphthalenes in Cigarette Smoke.  Anal. Chem., 48(4):645-
      650, 1976.

 [403] Argus, M. F., and J. C. Arcos.  Hydrocarbon-Nitrosoamine
      Synergism as a Possible Amplying Factor in Lung Turmori-
      genesis by Tobacco Smoke.  J. Theor. Biol.,  56 (2) :491-498,
      1976.

 [404] Bock, F. G.  Cocarcinogenic Activity of Nicotine.  Proc. Am.
      Assoc. Cancer Res., 17:2, 1976.

 [405] Etiology of Nasopharyngeal Carcinoma.  Lancet, 2 (8000) :1393,
      1976.

 [406] DeMicco-Pagis, C., et al.  Pathologic and Ultrastructural
      Investigation of a DMBA-Induced Transplantable Melanoma
      in the Golden Hamster.  Bull Cancer  (Paris), 63(l):73-86,
      1976.

 [407] Stepanova, L. G., et al.  DNA Reparation and Chromosome
      Aberrations in Human Cells Infected with LPV Oncornavirus.
     Vopr. Virusol.,  (6):712-716, 1977.
                               234

-------
was observed when mice, after successive infections with three
mouse-adopted strains of influenza and exposure to ozonized
gasoline aerosol, developed lung cancer  [408] .

INDUSTRIAL CHEMICALS AND POLLUTANTS

There is not a clear distinction between industrial chemicals
and industrial pollutants because in most cases the chemicals
produced and used by industry may also be discharged to the
environment.  Tests on rats have suggested a  synergistic effect
between inhaled vinyl chloride  (the monomer used  in producing
polyvinyl chloride) and ingested alcohol in tumorigenesis  [359].

There has been some concern over the solvents  employed in  testing
carcinogens as to their potential cofactor effect.  Many of these
solvents are also industrial chemicals,  and the findings of test
programs may also relate to industrial exposure.  Benzene,
toluene, and acetone were tested in this regard and it was con-
cluded that benzene and toluene have cocarcinogenic potency while
acetone had no effect  [409].  Acetone has been reported by others
as cocarcinogenic  [4].

Other  solvents which have been  tested include decalin, n-dodecane,
and 1-dodecanol.   In these  tests n-dodecane,  decalin and 1-dode-
canol  were  found  to be  cocarcinogenic solvents depending on the
concentration of  the carcinogenic materials used  [B(a)P and benzan-
thracene]  [410].   It has also been  reported that  the use of n-
dodecane as a solvent  for B(a)P can result in a 1,000-fold
enhancement of the effective concentration of B(a)P for skin
tumor  induction  [341].  Other studies confirm the cocarcinogenic
properties  of these materials,  including n-decane and  tetradecane
with B(a)P  and UV light  [411, 412].
 [408]  Bryan,  W.  R.   Current Concepts of Viral Neoplasia.   South.
       Med.  J.,  57(11):1263-1267,  1964.
 [409]  Mazzucco,  K.   The Effect of Various Solvents  (Benzene,
       Toluene,  Acetone)  Used with Carcinogens on the  Collagen
       Content of the Mouse Dorsal Skin.  Osterr. Z. Onkol.,
       2(2-3):49-51,  1975.
 [410]  Bingham,  E.,  and H.  L. Falk.  Environmental Carcinogens,
       The  Modifying  Effect of Cocarcinogens on the  Threshold
       Response.   Arch. Environ. Health, 19(6):779-783,  1969.

 [411]  Bingham,  E.,  and P.  J. Nord.  Cocarcinogenic  Effects of
       n-Alkanes and  Ultraviolet Light on Mice.  J.  Natl.  Cancer
       inst.,  58 (4) :1099-1101, 1977.
 [412]  Tanaka, T.   Influence of n-Dodecane on Rats Exposed Trans-
       placentially to Benzo(a)pyrene and Nitrosomethylurethan
       During  Pregnancy (Meeting Abstract).  Third International
       Symposium on Detection and Prevention of Cancer,  1976.
       pp.  286-287.


                                235

-------
A mineral oil (Drakeol 6VR) was analyzed and consisted of three
major components, one containing promoters  (e.g., hexadecane),
another containing mainly inhibitors, and the third containing
both promoters and inhibitors  [413].  Carbon tetrachloride, a
widely used solvent  (e.g., cleaning, fire extinguishers), has
been tested on rats and is suspected of acting as a cocarcinogen
in formation of liver tumors  [414] .

Total phenols from waste waters of a shale processing plant
applied to mouse skin after a subcarcinogenic dose of B(a)P
resulted in development of malignant neoplasms [415].  Others have
also reported the cocarcinogenic activity of phenols and anthralin
(1,8,9-anthracenetriol) used in the textile industry  [344, 416,
417].  Investigation into the frequency of cancers in an aldehyde
factory suggest that there may be a syncarcinogenic effect between
some aliphatic aldehydes  (which are also present in automobile
exhaust and cigarette smoke) and some air pollutants  [418].

Because dodecylbenzene has been reported to be a cocarcinogen and
tumor promoter [341, 419] a group of Russian scientists have
tested Sulfonol NP-1, a surfactant made from dodecylbenzene
sulfonate, for its potential cocarcinogenicity.  Sulfonol NP-1,
a mixture of sodium salts of alkylbenzene sulfonic acids, sodium
sulfate, and nonsulfonated organic compounds, acted as a
 [413] Horton, A. W.  Cellular Mechanisms of Chemical Carcino-
      genesis.  National Technical Information Service No. PB
      225 631, 1973.  91 pp.

 [414] Mori, H., et al.  Effect of Carbon Tetrachloride on
      Carcinogenicity of Petasites Japonicus, and Transplant-
      ability of Induced Tumors.  Gann, 68 (6) :841-845, 1977.

 [415] Mirme, H.  Modifying Effect of Water-Soluble Shale Phenols
      on Carcinogenesis.  Vopr. Profil. Zagryaz. Okruzhayushchei.
      Chel. Sredy Kantserogennymi Veshchestvami; 16-18, 1972.

 [416] Hecker, E.  Aspects of Cocarcinogenesis.  In:  Scientific
      Foundations of Oncology, T. Symington and R. L. Carter,
      eds., William Heinemann Medical Books,  Ltd., Chicago,
      1976.  pp. 310-318.

 [417] Falk, H. L.  Possible Mechanisms of  Combination Effects  in
      Chemical Carcinogenesis.  Oncology,  33(2):77-85, 1976.

 [418] Pershagen, G., et al.  Mortality in  a Region Surrounding an
      Arsenic Emitting Plant.  Environ. Health Perspect.,  19:133-
      137,  1977.

 [419] Gargus, J. L., et al.  Utilization of Newborn Mice in  the
      Bioassay of Chemical Carcinogens.  Toxicol. Appl. Pharmacol.,
      15(3):552-559, 1969.


                                236

-------
cocarcinogen but did not exhibit carcinogenic properties  [420].
Another surface-active agent, olefine sulphate, has been  tested
and demonstrated to enhance B(a)P induced skin cancer  [421].

The flame retardants tetrakis(hydroxymethyl)phosphonium chloride
(THPC) and Pyroset TKP  (mixed acetate/phosphate of same phos-
phonium base) have been tested on mouse skin and found to be
active as tumor promoters with DMBA initiation  [422].  THPC and
Pyroset TKP have been widely used in cotton fabrics, particularly
children's sleepware.  Other chlorinated compounds found  to
exhibit cocarcinogenic properties include polychlorinated bi-
phenyls (PCBs) and certain pesticides and herbicides.  Chloro-
phenol pesticides and the herbicide 2,4-D  (amine salt of
2,4-dichlorophenoxyacetic acid) were tested on mice and rats and
are suggested as potential cocarcinogens  [423, 424].  Similar
results were obtained from tests on PCB and DDT  [425, 426].

As with all agricultural products, pesticides and herbicides,
besides being industrial chemicals and pollutants, also result in
human exposure during usage and through the food chain.  Ammonia,
found in many chemical products including fertilizers, has been
tested on mouse cells as ammonium salts and a number of primary
 [420] Sakharov,  I.  I.,  et  al.   The  Cocarcinogenic Activity of
      Sulfonol NP-1.  Gig.  Tr.  Prof.  Zabol.,  (9):56-58, 1973.

 [421] Pyleva, Z. A.,  et al.   Data on  the  Biological Properties of
      Olefin Sulfate.   Vopr.  Onkol.,  24(1):55-60, 1978.

 [422] Loewengart, G., and  B.  L.  Van Duuren.   Evaluation of
      Chemical Flame  Retardants for Carcinogenic Potential.
      J. Toxicol. Environ.  Health,  2(3):539-546, 1977.

 [423] Arrhenius, E.,  et al.   Disturbance  of Microsomal Detoxica-
      tion Mechanisms in Liver  by Chlorophenol  Pesticides.   Chem.
      Biol. Interact.,  18(l):35-46, 1977.

 [424] Arkhipov,  G.  N.,  and I. N. Kozlova.  Study of the Carcino-
      genic Properties  of  the Herbicide,  Amine  Salt of 2,4-
      Dicholorphenoxyacetic Acid.   Vopr.  Pitan. ,  (5):03-84,  1974.

 [425] Uchiyama,  M., et  al.   Cocarcinogenic Effect of  DDT  and PCB
      Feeding on Methylcholanthrene-Induced Chemical  Carcino-
      genesis.   Bull. Environ.  Contam.  Toxicol., 12(6):687-693,
      1974.

 [426] Nagasaki,  H., et  al.   Analysis  of Various Factors on Liver
      Carcinogenesis  in Mice Induced  by Benzene Hexachloride (BHC)
      and Technical Polychlorinated Biphenyls (PCBs).  J. Nara.
      Med. Assoc.,  25(6):635-648,  (Reed.  1975).


                                237

-------
amines.   The evidence implied that ammonia may be carcinogenic or
cocarcinogenic [427] .

Orthophosphate and 1-phenylalanine were tested on hamster cheek
pouches and found to promote tumor growth.  Phenylphosphate, on
the othtr hand, inhibited carcinogenesis  [428].  Chromium car-
bony 1, when tested on rats, was demonstrated to be a carcinogen
and acted synergistically with B(a)P [429].  Results of tests
with sodium hypochlorite show that it is cocarcinogenic; however,
it was concluded that this chemical is not a practical carcino-
genic hazard  [430].  Repeated application of hydrogen peroxide
after application of B(a)P to mouse skin markedly inhibited the
carcinogenicity of B(a)P [431].

Other industrial chemicals have been tested and found to be
carcinogenic cofactors.  Four chemical substances, N-nitrosopiper-
idine, N-nitrosomorpholine, diethylnitrosoamine, and N-2-
fluorenylacetamide) were fed to mice for 4 weeks.  Each substance
inhibited the induction or urinary bladder cancer by n-butyl-N-
(4-hydroxybutyl)nitrosoamine [325].  In tests on oral carcinogens
it was found that 2-aminonaphthalene and 4-nitrobiphenyl were
very synergistic in the development of bladder cancer in dogs
[432].  When two chemicals of the same organotropy  (affecting
the same organs), such as  the liver carcinogens diethylnitroso-
amine and 4-dimethylaminoazobenzene, were applied to mice, the
effect was synergistic.  Syncarcinogenesis was not observed,
however, when chemical carcinogens of differing organotropy were
tested simultaneously.
 [427] Capuco, A. V.  Amonia:  A Modulator of 3T3 Cell Growth.
      Diss. Abstr. Inst.  (B), 38(9):48085, 1978.

 [428] Rubin, D., and I. S. Levij.  Chemical Carcinogenesis  in the
      Hamster Cheek Pouch:   Influence of Inhibitors and  Inducers
      of Alkaline Phosphatase.  Pathol. Microbiol.  (Basel),
      43 (1) :26-30, 1975.

 [429] Lane, B. P., and M. J. Mass.  Carcinogenicity and  Cocarcino-
      genicity of Chromium Carbonyl in Heterotopic Tracheal Grafts,
      Cancer Res., 37 ( 5) :1476-1479, 1977.

 [430] Hayatsu, H., et al.  Potential Cocarcinogenicity of Sodium
      Hypochlorite.  Nature  (Lond.) , 233 (5320) :495, 1971.

 [431] Nagata, C., et al.  Effect of Hydrogen Peroxide, Fenton's
      Reagent, and Iron Ions on the Carcinogenicity of 3,4-
      Benzopyrene.  Gann, 64 (3) : 277-285, 1973.

 [432] Deichmann, W. B., and  J.  L.  Radomski.  Synergism Among Oral
      Carcinogens and Tumorigens,  Report of Preliminary  Experi-
      ments.  Toxicol. Appl. Pharmacol., 6(3) :343-344 , 1964.
                                238

-------
Other chemical substances of potential industrial exposure have
been investigated through medical histories of people employed
in manufacturing operations or exposed to the chemical substance.
The lungs of 100 consecutive patients at autopsy and 24 patients
with pulmonary neoplasms were analyzed.  More than 90% of the
patients from both groups had ferruginous  (asbestos) bodies in
their lungs with no apparent difference in the incidence or
quantity between the randomly selected group and those with
pulmonary neoplasms.  This supports the view that asbestos acts
as a cocarcinogen in causing pulmonary neoplasms.  These find-
ings also indicate that asbestos dust contamination is widespread
throughout rural and urban environments  [433].

In a review of toxic challenges to the lung, mention is made of
the synergism between quartz and environmental irradiation.  How-
ever, about tenfold fewer workers with occupationally heavy dust
exposure died of bronchial carcinoma than men of equivalent age
in the general population  [434].  Fibrous glass, whose cancer-
causing potential has been established in animal studies, is
postulated to act as a cocarcinogen with cigarette smoke and
other carcinogens when inhaled  [435].

An investigation of chromatid aberrations among smelter employees
exposed to arsenic showed a significantly increased frequency in
employees versus controls.  However, a cocarcinogenic action of
arsenic with cigarette smoking was proposed to be responsible for
the poor correlation between frequency of aberrations and arsenic
exposure  [436].  The results of animal testing with arsenic
trioxide, metal ore, and refinery flue dust indicated that solid
arsenical substances acted cocarcinogenically with B(a)P [437].
Experimental results from exposing rats to beryllium oxide and
carbon black with a known carcinogen showed both to be tumor
 [433] Breedin,  P.  H.,  and  D.  H. Buss.  Ferruginous  (Asbestos)
      Bodies  in the  Lungs  of  Rural Dwellers, Urban  Dwellers, and
      Patients  with  Pulmonary Neoplasms.  South. Med. J.,
      69(4) :401-404,  1976.

 [434] Einbrodt,  H. J.   Combined Effort of Fine Dust on the Lung.
      Staub Reinhaltung Luft, 36 (3) : 122-126 , 1976.

 [435] Rom, W. N.,  and  A. M. Langer.  Carcinogenicity of Fibrous
      Glass  (Letter  to Editor).  West. J. Med.,  126(5):413,  1977.

 [436] Nordenson,  I.,  et al.   Occupational and Environmental  Risks
      in  and  Around  a  Smelter in Northern Sweden, II.  Chomosomal
      Aberrations  in Workers  Exposed to Arsenic.  Hereditas,
      88(1):47-50, 1978.

 [437] Ishinishi,  N.,  et al.   Preliminary Experimental Study  on
      Carcinogenicity  of Arsenic Trioxide in Rat Lung.  Environ.
      Health  Perspect.,  19:196-196,  1977.


                               239

-------
promoters with beryllium being the more potent promoter  [438] .
Several studies conducted on hamsters have demonstrated that
iron oxide (Fe203)  dust enhances chemically induced carcinogeni-
city [439, 440].

Peracet c acid, perbenzoic acid, and m-chloroperbenzoic acid were
found to be active tumor promoters in skin carcinogenesis when
tested on rats [441].   Pyran copolymer has been tested on mice
and found to promote B(a)P induced skin tumors  [442].

One of the more important categories of environmental pollution
is the area of combustion products.  Because combustion operations
are widely scattered throughout the population, human exposure
cannot be avoided.   Sulfur dioxide (S02)f which is emitted from
combustion sources firing sulfur laden fuel (coal, oil), showed
significant cocarcinogenic effects with B(a)P, another combustion
product, in animal experiments  [443].

Studies on trace elements, emitted from most fossil fuel combus-
tion systems, especially coal-fired units, have produced somewhat
contradictory results.  In vitro tests on a series of trace
elements indicated that some trace elements have have a cocarcino-
genic effect in B(a)P induced cancer  [444].  Another study on
mice concluded that there was no evidence of trace element
 [438] Uzawa, T.  Histopathological Studies on Pulmonary Reaction
      by Beryllium Oxide in Rat  (Experimental Tumorous Action of
      BeO Combined with Carcinogenic Hydrocarbons).  Bull. Tokyo
      Med. Dent. Univ., 9(3):440, 1963.

 [439] Nettesheim, P., et al.  Carcinogenic and Cocarcinogenic
      Effects of Inhaled Synthetic Smog and Ferric Oxide Par-
      ticles.  J. Natl. Cancer Inst. , 55 (1) :159-169, 1975.

 [440] Sellakumar, A., et al.  Effects of Different Dusts on
      Respiratory Carcinogenesis in Hamsters Induced by Benzo-
      (a)pyrene and Diethylnitrosoamine.  Eur. J. Cancer,  12(4):
      313-319, 1976.

 [441] Bock, F. G., et al.   Cocarcinogenic Activity of Peroxy
      Compounds.  J. Natl.  Cancer Inst., 55 (6) :1359-1361,  1975.

 [442] Kripke, M. L., and T. Borsos.  Accelerated Development of
      Benzo(a)pyrene-Induced Skin Tumors in Mice Treated with
      Pyran Copolymer.  J.  Natl. Cancer Inst., 53(5):1409-1410,
      1974.

 [443] Shapiro, R.  Genetic  Effects of Bisulfite  (Sulfur Dioxide)
      Mutat. Res.P 39 (2) :149-176, 1977.

 [444] Galop, J., et al.  A  Study of the Influence of Trace
      Elements on the Hydroxylation of Benzo(a)pyrene.  Eur. J.
      Toxicol. Environ. Hyg., 9(5):271-286, 1976.

                                240

-------
cocarcinogenesis with 3-methylcholanthrene  [445].  Lead oxide, an
emission from automobiles buring leaded gasoline, was  tested on
hamsters with B(a)P as the carcinogenic substance.  Results
suggested that lead oxide is a cocarcinogenic material  [446].
Lead oxide is also found in and around lead  smelters and battery
plants.

Polycyclic hydrocarbons  (PCH) are also emitted  from most combus-
tion systems.  They are products of  incomplete  combustion and are
emitted in greater quantities from the less  efficient  combustion
equipment.  A number of compounds in this class  of material are
considered carcinogenic; this has stimulated studies on the
possible cocarcinogenic effect of PCH.

3-Methylcholanthrene  (MCA) and dimethylnitrosoamine (DMN) were
tested on mice and found to act synergistically, resulting in
enhancement of lung cancel and kidney tumors [447].  However,
MCA has also been reported to inhibit or prevent tumorigenesis
induced by carcinogenic aromatic amines or azo  dyes [448].  Nitro-
soamines such as diethylnitrosoamine  (DEN) and  DMN can be formed
from nitrous compounds emitted to the atmosphere.  These compounds
have been tested on mice by others and found to  be cocarcinogenic
in the lung  [449].

Usually considered to be a noncarcinogenic PCH,  benzo(e)pyrene
[B(e)P] has been reported to act as  a cocarcinogen when applied
to mouse skin with B(a)P.  However, when tested  in a respiratory
tract tumor model, B(e)P did not act as a cocarcinogen and may
have inhibited B(a)P  carcinogenicity  [450].  Three other PCH
 [445] Shimkin, M. G.,  et  al.   Lung Tumor Response  in Mice to
      Metals and Metal Salts.  Adv. Exp. Med. Biol., 91:85-91,
      1977.
 [446] Kobayashi, N.,  and  T. Okamoto.  Effects of Lead Oxide on
      the  Induction of Lung Tumors in Syrian Hamsters.  J. Natl.
      Cancer Inst., 52 (5) :1605-1610, 1974.

 [447] Cardesa, A., et al.  The Syncarcinogenic Effect of Methyl-
      cholanthrene and Dimethylnitrosoamine in Swiss Mice.
      Z. Krebsforsch.,  79 (2) :98-107, 1973.

 [448] Danz, M., et al.  Prevention of 2-Acetylaminofluorene-
      Induced  Extrahepatic Short-Term Effects by 3-Methyl-
      cholanthrene.   Exp.  Pathol.  (Jena),  13 (4-5) :262-267 , 1977.

 [449] Cardesa, A., et al.  Effects of Intraperitoneal Injections
      of Dimethyl- and Diethylnitrosoamine, Alone  or Simultaneously
      on Swiss Mice.   Z.  Krebsforsch.,  82(3) :233-238, 1974.

 [450] Topping, D. C.,  et  al.   The Interaction of Benzo(a)pyrene
      and  Benzo(e)pyrene  in Respiratory Tract Carcinogenesis
       (Meeting Abstract).  Proc. Am. Assoc. Cancer Res.,  19:43,
      1978.


                                241

-------
carcinogenic compounds [MCA, B(a)P, and DMBA] were tested in
subeffective concentrations to determine the synergistic action
of any two compounds.  All combinations of any two of these
compounds exhibited a synergistic action [451].

Ozone, ^ secondary pollutant, results from the photo-oxidation of
primary combustion pollutants such as nitrogen oxides and hydro-
carbons.  Tests on hamsters exposed to ozone followed by B(a)P
resulted in B(a)P induced lung cancer with ozone acting as a
cocarcinogen [452].   The cofactor effects of industrial chemicals
and pollutants are summarized in Table B-2.

ESOTERIC MATERIALS AND OTHER SUBSTANCES

Several substances have been found that act as carcinogenic co-
factors, but they have little or no potential for human exposure
and are employed mainly as research substances.  A prime example
is croton oil which has been found to be a strong promoter and
can be relied upon to exhibit promoting properties when studying
cancer mechanisms or substances suspected of initiating carcino-
genesis.  Croton oil, a plant extract  (Euphorbiaceae), has been
reported to act mainly as a promoter  [344, 453] but has also been
reported as a cocarcinogen  [345].  Possibly the difference is
actually caused by a misuse in terminology.

Several other studies have reported substances related to the
Euphorbiaceae plant family that also acted as promoters or
cocarcinogens.  Latex samples from a plant in this family showed
toxic and cocarcinogenic activity traceable to a palmitic acid
ester of a polyfunctional diterpene  [454].  A followup study
confirmed the cocarcinogenic activity of diterpene esters of
Euphorbiaceae  [455].  TPA  (12-0-tetradecanoylphorbol-13-acetate),
sometimes referred to as PMA  (phorbol myristate acetate), is also
a substance from the Euphorbiaceae family which has been reported
 [451] Mondal, S., et al.  Syncarcinogenesis in Culture C3E/IOTh
      Cells  (Meeting Abstract).  Proc. Am. Assoc. Cancer Res.,
      18:8, 1977.
 [452] Palmer, M. S., et al.  Effect of Ozone on Benzpyrene
      Hydroxylase Activity in the Syrian Golden Hamster.  Cancer
      Res., 31(6):730-733, 1971.
 [453] Sellakumar, A. R., et al.  Influence of Croton Oil in
      Hamster Lung Carcinogenesis.  Proc. Am. Assoc. Cancer Res.,
      16:57, 1975.

 [454] Hecker, E.  Cocarcinogenic Agents Derived from Euphorbiaceae,
      Planta. Med., 1968:24-25, 1968.

 [455] Hecker, E.  New Toxic, Irritant, and Cocarcinogenic
      Diterpene Esters from Euphorbiaceae and from Thymelaeceae.
      Pure Appl. Chem., 59 ( 9) :1423-1431, 1977.


                                242

-------
                            TABLE  B-2.
                                       INDUSTRIAL  CARCINOGENIC  COFACTORS AND  THEIR
                                       EFFECTS  WITH  SOLITARY  CARCINOGENS
                                                     Cofactor effect
                Cofactor
                                   Promoter   Cocarcinogen   Syncarcinogen    Inhibitor
                                                                                        Solitary  carcinogen or  initiator
U)
Asbestos
Quartz
Fibrous glass
Arsenic
Berryllium oxide
Carbon black
Iron oxide
Peracetic acid
Perbenzoic acid
m-Chloroperbenzoic acid
Sulfur dioxide
Ozone
Trace elements
Lead oxide
3-Methycholanthrene
3-Methylocholanthrene
Benzo(e)pyrene
Benzo(e)pyrene
Environmental carcinogens
Environmental irradiation
Cigarette smoke
Cigarette smoke,  benzo(a)pyrene [B(a)P]
20-Methylcholanthrene
20-Methylcholanthrene
B(a)P, diethylnitrosoamine
(Known carcinogen)
(Known carcinogen)
(Known carcinogen)
B(a)P
B(a)P
B(a)P
B(a)P
DimethyInitrosoamine
Azo dyes, aromatic  amines
B(a)P (skin)
B(a)P (respiratory  tract)
                                                                                                                             (continued)

-------
TABLE  B-2  (continued).

Cofactor
Pyran copolymer
Vinyl chloride
Benzene
Toluene
Acetone
Decalin
n-Dodecane
1-dodecanol
n-Decane
n-Tetradecane
Mineral oil (Drakeol 6VR)
Carbon tetrachloride
Phenols
Anthralin
Aliphatic aldehydes
Dodecylbenzene
Sulfonol NP-1
Olefine sulfate
Cofactor effect
Promoter Cocarcinogen Syncarcinogen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Inhibitor Solitary carcinogen
B(a)P
Ingested alcohol
(Known carcinogen)
(Known carcinogen)
or initiator




Polycyclic aromatic hydrocarbons
B(a)P, benzanthracene
B(a)P, benzanthracene, UV
B(a)P, benzanthracene
UV light
UV light
X (Known carcinogen)
Petasite japonicus
B(a)P
(Known carcinogen)
Air pollutants
(Known carcinogen)
3-Methylcholanthrene
B(a)P

light











                                                      (continued)

-------
                                                      TABLE B-2  (continued).
                                                      Cofactor effect
                 Cofactor
                                    Promoter   Cocarcinogen   Syncarcinogen    Inhibitor
                                                                                        Solitary carcinogen  or  initiator
to
«*
Ln
Tetrakis(hydroxymethyl)-
  phosphonium chloride
Pyroset-TKP
Polychlorinated biphenyls
Chlorophenol
2,4-D herbicide
DDT pesticide
Ammonium compound
Orthophosphate
1-Phenylalanine
PhenyIpho spha te
Chromium carbonyl
Sodium hypochlorite
Hydrogen peroxide
N-nitrosopiperidine
N-nitrosomorpholine
Diethylnitrosoamine
N-2-fluorenylacetamide
2-Aminonaphthalene
4-Dimethylaminoazobenzene
7,12-Dimethylbenz(a)anthracene
7,12-Dimethylbenz(a)anthracene
Benzene hexachloride,  methylcholanthrene
(Known carcinogen)
(Known carcinogen)
Methylcholanthrene
(Known carcinogen)
9,10-Dimethyl-l,2-benzanthracene
9,10-Dimethyl-l,2-benzanthracene
9,10-Dimethyl-l,2-benzanthracene
B(a)P
4-Nitroquinoline-l-oxide
B(a)P
n-Butyl-N-(4-hydroxybutyl)nitrosoamine
n-Butyl-N-(4-hydroxybutyl)nitrosoamine
n-Butyl'-N- (4-hydroxybutyl) nitrosoamine
n-Butyl-N-(4-hydroxybutyl)nitrosoamine
4-Nitrobiphenyl
Diethylnitrosoamine

-------
to be cocarcinogenic [456-458].  Phorbol is the parent dieterpene
of TPA and is not cocarcinogenic [459].

Other reported promoters and cocarcinogens of unknown signifcance,
as far as potential human exposure, include 4-ethylsulfonyl-
naphthaleiie-1-sulfonamide (promoter)  [344], and n-butyl-N- (4-
hydroxybutyl)nitrosoamine,  N-[4-(5-nitro-2-furyl)-2-thiazolyl]
formamide, and 3,3'-dichlorobenzidine (cocarcinogens)  [460].
Inhibitors of unknown origin and unknown human significant include
alpha-naphthylisothiocyanate, p-hydroxypropiophenone  [323] ,
cis-aconetic acid, putrescine  [461], and elipticine  [462].
 [456] zor Hausen, H. Z., et al.  Persisting Oncogenic Herpesvirus
      Induced by the Tumour Promoter TPA.  Nature  (Lond.),
      272 (5651) :373-375, 1978.
 [457] Komitowski, D., et al.  Epidermal Intercellular Relationships
      During Carcinogenesis and" Cocarcinogenesis as Revealed by
      Scanning Electron Microscopy-  Virchows Arch.  (Cell Pathol.),
      24(4):317-333, 1977.
 [458] Janoff, A., et al.  Local Vascular Changes Induced by the
      Cocarcinogen, Phorbol Myristate Acetate.  Cancer Res.,
      30(10):2567-2571, 1970.
 [459] Soper,  C. J. , and F. J. Evans.  Investigations into the
      Mode of Action of the Cocarcinogen 12-0-Tetradecanoyl-
      phorbol-13-acetate Using Auxotrophic Bacteria.  Cancer
      Res.,  37(8, Part 1):2487-2491, 1977.
 [460] Tsuda,  H., et al.  Synergistic Effect of Urinary Bladder
      Carcinogenesis in Rats Treated With n-Butyl-N-(4-hydroxy-
      butyl)nitrosoamine, n-[4-(5-Nitro-2-furyl)-2-thiazolyl]-
      formamide, n-2-Fluorenylacetamide, and  3,3'-Dichloroben-
      zidine.  Gann, 68 (2) :183-192, 1977.

 [461] Kallistratos, G.  Prevention  of 3,4-Benzpyrene Carcino-
      genesis by Naturally Occurring and Synthetic Compounds.
      Meunch. Med. Wochenschr., 117(10):391-394, 1975.

 [462] Truhart, R., et al.  Inhibitor Effect of Ellipticine
      [Dimethyl-5, II-(6H) Pyrido  (4,3-B Carbazole)  on Rat Liver
      Carcinogenesis Induced by BT6  (n,n-Dimethyl-p-benzo-
      thiazolylazo) Aniline]:  Incidences on  Cytochrome P450 and
      Arginase Activity  (Meeting Abstract).   Fourth  Meeting of
      the European Association for  Cancer Research  (held at
      Universite de Lyon, September 13-15, 1977), European
      Association for Cancer Research,  Lyon,  France, 1977.  p.  86.


                               246

-------
                                   TECHNICAL REPORT DATA
                            (Please read IniLniciiuns on She reverse bcfon completing!
 1 REPORT NO
  EPA-600/2-80-015
 4 TITLE AMD SUBTITLE
 POTENTIAL ATMOSPHERIC  CARCINOGENS
 Phase 1.  Identification  and Classification
                                                           3. RECIPIENT'S ACCESSION-NO.
             5 REPORT DATE
                 January 1980
             6 PERFORMING ORGANIZATION CODE
 7 AbTHORlSi
 Carl R. McMillin,  Leland  B.  Mote,  and Daryl  G. DeAngelis
             8 PERFORMING ORGANIZATION REPORT NO.

              MRC-DA-870
 9 PERFORMING ORGANIZATION NAVE AND ADDRESS
 Monsanto Research  Corporation
 Dayton Laboratory
 1515 Nicholas  Road,  P.O.  Box 8,  Station B
 Dayton, Ohio   45407
             TO. PROGRAM ELEMENT NO.

               1HE7.75D  CB-005 (FY^79}_
             11. CONTRACT/GRANT NO.
              68-02-2773
 12. SPONSORING AGENCY NAME AND ADDRESS
 Environmental  Sciences  Research Laboratory -- RTP, NC
 Office of  Research  and  Development
 U. S. Environmental  Protection Agency
 Research Triangle  Park,  North Carolina  27711
             13 TYPE OF REPORT AND PERIOD COVERED
              Interim  9/77 -  10/78	
             14. SPONSORING AGENCY CODE
              EPA/600/09
 15. SUPPLEMENTAR l  NOTES
 16. ABSTRACT
 A comprehensive  literature search identified more than 125 high-volume chemicals  having
 the potential  of becoming airborne carcinogenic pollutants.  Based on carcinogenicity
 and mutagenicity data,  the pollutants were divided into three categories:  probable
 carcinogens,  possible  carcinogens, and probable noncarcinogens.   Additional data  were
 collected  for the possible and probable carcinogens including their annual production,
 emissions, atmospheric  persistence, and relative mutagenic and carcinogenic potencies.
 The pollutants were  then  ranked on the basis of a calculated equivalent weight of
 benzo(a) pyrene  emitted per year after 24 hours in the atmosphere.  From the top
 portions of these two  lists, 20 compounds, representing various  chemical classes,
 were chosen for  future  analysis.  A state-of-the-art review of the effect of cofactors
 on the carcinogenicity of chemicals was also completed.  To locate optimum sampling
 sites in cities  of interest, a series of carcinogen isopleths was generated.  Using
 information such as  the locations of stationary sources of carcinogenic pollutants,
 normalized wind  direction and speed, and the height, temperature, and rate of flow
 of the sources,  the  probable locations of maximum carcinogenic pollution concentration
 were computed.
17.
                                KEY WORDS AND DOCUMENT ANALYSIS
                  DESCRIPTORS
                                              b.IDENTIFIERS/OPEN ENDED TERMS
                                                                          COSATI Held'Group
 *Air pollution
 *Carcinogens
 *Reviews
 identifying
                                  13B
                                  06E
                                  05B
 5 DISTRIBUTION STATEMENT
 RELEASE TO PUBLIC
19, SECURITY CLASS (This Report/

  UNCLASSIFIED
                                                                        21  NO. OF PAGES

                                                                               253
                                              20 SECURITY CLASS {Thispagc/
                                               UNCLASSIFIED
                          22 PRICE
EPA Form 2220-1 (9-73)
                                            247

-------