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