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EXECUTIVE SUMMARY
Aromatic amines and compounds related through metabolism are
used widely in industry. AS a result of such applications, they are
also dispersed into the environment, thereby creating a potential
for human exposure. Four aromatic amines are known to lead to
ur inary tract cancer in exposed humans, and some are also
responsible for the induction cuff methemoglobinemia. Some other
structurally similiar amines are carcinogenic to one or more tissues
in laboratory animals.
His report summarizes the key information concerning the
occurrence, analysis, and toxicology of the aromatic amines and then
considers six specif ic amines in detail.
H I STORICAL PERSPECTIVE
Aromatic amines compr ise one Of the ma jor groups of
carcinogens. In 1895 Rehn reported that four workmen, three of whom
were employed at a single plant manufacturing magenta (fuschin) from
crude, coT'unercial aniline, appeared at his Olin ic with bladder
cancer . He cor rectly deduced that these comparatively rare tumors
were associated with the workers' occupation. Hueper (1942)
suggested that a limited number of aromatic amines were human
bladder carcinogens in humans. Case and his colleagues {1954}
confirmed this finding in their classic investigation of the British
chemical industry. Hey demonstrated that 2-naphthylamine,
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benzidine, and 1-naphthylamine, contaminated with between 4% and 1096
of the 2-isomer, were carcinogenic in the human bladder. Melick and
his associates (1955, 1971) also showed that 4-aminobiphenyl
(xenylamine) was a potent carcinogen in the bladders of those
occupationally exposed and of users.
The only other aromatic amine for which there is significant
evidence of probable carcinogenicity in humans is
4-ethoxyacetanilide (phenacetin), which was a major component of the
analgesics consumed in excessively large quantities by certa in
well-defined populations. These exposed populations developed renal
papillary necrosis and renal pelvic and bladder cancer (Bengsston et
al., 1968; Rathert et al., 19731.
Two consequences followed the identification of bladder
carcinogens in occupationally exposed humans. First, the
manufacture and use of 4-aminobiphenyl and 2-naphthylamine have, for
all practical purposes, been phased out, although benzidine
continues to be manufactured and used, even in the United States.
Traces of a variety of aromatic amines, including 2-naphthylamine,
still occur in the environment as the result of combustion of
organic materials, including cigarettes. Second, there has been a
ma jor research ef fort to determine which aromatic amines are
carcinogenic in laboratory experimental animals {Clayson and Garner,
1976 ), how they may be measured in the environment, and how their
m.~ charism of action operates {Miller and Mills , 19-') . Results
from this effort demonstrate that many aromatic amines or their
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derivatives are indeed potent carcinogens in animals and that they
are converted to derivatives of arylhydroxylamines during metabolic
activation. me se intermediates probably dissociate to
electrophilic nitrenium ions which interact with nucleophilic
centers in major cell macromolecules (e.~., DNA, RNA, and protein}
in exerting their carcinogenic and other toxic effects.
CHARGE TO THE COMMITTEE
The committee was convened by the National Research Council at
the request of the Environmental Protection Agency (EPA) to assess
the health and environmental effects of amines. The committee
decided that the topic could be addressed best by dividing the
subject into two parts: (1) aromatic amines and related compounds
and (2) aliphatic amines. This report on aromatic amine s consists
of chapters on the general characteristics of the class followed by
chapters concerned with specif ic chemicals that illustrate problem
areas .
The committee reviewed the background information on aromatic
amines and related compounds, stressing, for example, general
analytic methods, toxicity, mutagenic and carcinogenic properties,
and the utility of these substances to industry. It decided that it
would exclude chemicals such as 2-naphthylamine, 4-aminobiphenyl and
benzidine since they have been extensively and repeatedly reviewed
in the past. Benzidine and its cogeners were especially well
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covered in a recent report by Shriner et al. (1978).
Discussions with the EPA led to the selection of the following
compounds for intensive review: aniline,
4,4'-methylenebis(2-chloroaniline), 2,4-diaminotoluene, trifluralin
and oryzalin, ~cresidine, and furazolidone. Both trifluralin and
furazolidone are nitro compounds, but were considered relevant to
this study because of the relatively easy biological conversion of
the nitro groups to the amino group and the fact that
arylhydroxylamine der ivatives, in which the nitrogen is in an
intermediate oxygenated state between the amine and nitro compound
forms, is now generally recognized as the proximate biologically
active form.
The committee did not address the environmental aspects of
exposure after an intensive search of the literature revealed a lack
of information on this subject for the compounds selected.
OCCURRENCE, CONTROL, AND ANALYTIC METHODS
.
Aromatic amines are used in dyes, antioxidants, polymers,
explosives, pesticides, and pharmacolog ic agents. Workers in plants
prod uc ing these products can be exposed to a health hazard. An
evaluation of the da ta indicating that aromatic amines are
potentially toxic in humans indicates that it is prudent to suggest
that exposure be held to a minimum both for the worker and others
who may be exposed to inadequately controlled wastes associated with
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Representative terms from entire chapter:
bladder cancer
manufacture of the products or who are users of the products. Low
levels of exposure to aromatic amines may result from the products
of destructive distillation of materials containing carbon,
hydrogen, and nitrogen, as in smoke from tobacco and the gases
resulting f rom the combustion of foss il fuels. Because of the
anticipated changes in the consumption pattern of fossil
fuels--those impl ic it in the promotion of diesel eng ines and the use
of coal--occupational and environmental exposure to the aromatic
amines may increase (National Academy of Sciences, 1981~. The
committee recommends that both the qualitative and
Other metabolic reactions, such as acetylation and ring hydroxylatiOn
followed by con jugation, are detoxifying pathways.
Understanding of the metabolism of aromatic amine s in laboratory
animals has advanced to the point that research workers are better
able to understand the process in humans. To further this objective,
it is first necessary to know which animal most closely approximates
the metabol ic responses of humans. Assuming that most chemical
carcinogens need to be metabolized in the host to active forms in
order to exer t a carcinogen ic effect, it becomes necessary to know
how specif ic carcinogens are activated in animals. If the metabolism
of a specif ic chemical carcinogen in human tissues is qualitatively
simil far to that observed in studies of tissues from a susceptible
test animal, then a potential carcinogenic effect might also be
observed in humans exposed to the chemical . Al though the use of
humans for testing is difficult or impossible and laboratory animals
tests are expensive, it should be feasible to make inferences
concerning responses in humans based on In vitro tests with Truman
cell lines, mutagenicity testing with human liver S-9 fractions, and
careful monitoring of blood and urine of humans accidently exposed to
compounds of interest. It would be easier to assess the risk to
humans from many aromatic amines if additional biological data on
occupationally or otherwise exposed humans were obtained.
STRUCTURE-ACTTVI TY RELATIONSHIPS
Many aromatic amine and nitro compounds exhibit the ability to
induce cancer in animals. Unless polar groups, such as sulfonic or
6
carboxylic acid substituents, are present in the molecule, these
chemicals should be regarded as potentially carcinogenic. FortunatelY'
however ~ the most potent carcinogens among Me aromatic amines appear
to possess certa in structural identifying character istics, such as:
o one, two, or three conjugated aromatic ring systems,
o an aromatic amino group substituted in the position pare to the
conjugated aromatic system; or
0 groups, such as methyl, methoxyl, or fluorine, substituted in
relative positions to the amino group.
However, carcinogenicity has been associated with aromatic amines that
lack one or more of these character istics.
A thorough understanding of these relationships may make it
possible to predict the potential toxicity of aromatic amines before
they are adopted for widespread use. Furthermore, this knowledge and
the ant icipated increases in the understanding of structure-activity
characteristics of aromatic amines and of other chemicals may allow for
the selective development of desirable chemical species without the
accompanying toxicity.
CARC INOGENIC POTENCY AND RISK ESTIMATION
-
It is not yet possible to predict the potency of a carcinogen in
any species. One prudent approach is to assume that humans are at
least as sensitive to these carcinogens as are the most sensitive
species. For example, 2-naphthylamine should be assumed to be as
7
potent in humans as it is in dogs.
The potency of a carcinogen depends on three factors: the done of
carcinogen required to induce tumors, the time to tumor induction,
and the percentage tumor response. A method for expressing relative
potency is described in Chapter 4. Whatever tOmor incidence-dose
model is used to descr ibe a biolog ic event, the suggested means of
expressing potency values discussed herein may have a considerable
advantage in that these values may be derived without excessive
effort or data extrapolation. Ways of predicting carcinogenic
potency based on the present knowledge of the mechanisms of
carcinogenesis urgently need to be improved.
The use of statistical models to estimate possible risk to humans
exposed to very low concentrations is filled with uncertainty.
Studies of animals usually involve exposure to a high level of a
single carcinogen and, sometimes, just one modifying agent. On the
other hand, humans are exposed to a wide range of carcinogens and
carcinogenesis-modifying agents that may enhance or inhibit the
development of cancer especially if the carcinogen exposure is low.
The recently completed EDo1 exper iment conducted by the
National Center for Toxicological Research has forced a rethinking of.
some aspects of dose-response modeling for carcinogenesis. More
attention may need to be directed toward the concepts of initiation
and promotion and the inherent abilities of chemicals to act in one
or the other capacity as well as in both.
8
EP IDEMIOLOGY
Occupational exposure to 4-aminobiphenyl, 2-naphthylamine, and
benzidine has been clearly associated with an increased rate of bladder
cancer in workers. The use of 2-naphthylamine-containing ingredients
in the British rubber industry was associated with bladder cancer in
workers; however, U.S. rubber workers have not exhibited an increased
incidence of bladder cancer as a result of exposure to that compound.
There is no epidemiologic evidence from which to assess the effects on
humans from exposure to the specific chemicals examined in this report.
With the exception of trifluralin, the chemicals assessed in this
report have induced cancer at various sites in one or more species of
animals. Most toxicologists accept the concept that a demonstration of
carcinogenicity in laboratory animals implies that the causative agent
is a potential carcinogen in humans. Of the chemicals discussed in
this report, 2,4-diaminotoluene (a component of some hair dyes) and
4,4'-methylene-bis(2-chloroaniline) (MOCA) are of most interest because
they have been shown to be carcinogen ic in animals and because humans
are frequently exposed to products containing them. Case-control
studies have raised suspicions, while not providing conclusive proof,
that the use of widely available hair dyes containing
2!4-diaminotoluene may be associated with cancer of the breast and of
other sites. Because of faulty industr ial waste disposal methods, many
people in Adrian, Michigan have been exposed to MOCA, which is known to
be a potent carcinogen in animals. However, there is little evidence
upon which to judge its carcinogenicity or other effects to humans.
9
Retrospective studies are not as likely to provide definitive
information on carcinogenicity in humans. In case-control studies of
cancer, the recollection of, for example, hair dye use is subject to a
high degree of recall bias. In retrospective cohort studies of persons
exposed to other chemicals, there is a very imprecise measure of
exposure.
The prospective follow-up study is the only realistic study design
to evaluate the carcinogenicity of these substances in humans. To
determine the ef feats of ha ir dyes, it would be necessary to interview
women (and possibly men) about their lifetime use of hair dyes and
follow them for 5 to 20 years to measure the rate of cancer occurrence.
To determine MOCA's health effects, persons exposed occupationally to
relatively high levels of MOCA, their families, and preschool children
living near the plant would have to be identified, categorized as to
level of current (and future ~ exposure, and followed for 20 to 40 years.
The epidemiolog ic evaluation of the possible health effects from
exposure to low levels of aromatic amines as well as to other substances
may be costly and time consuming. To the extent that disease among an
exposed group is increased relatively little above background, perhaps
less than 50%, the excess may not be detectable against the background
variability. One of the best ways to minimize this variability is to
conduct prospective follow-up studies, so that the measure of exposure
is as precise as possible and does not, for example, depend on
memory-based recall of hair dye use. If this strategy is adopted, long
term and costly follow-up is the price that must be paid.
10
ANILINE
In the United States, more than 300 x 103 metric tons of
aniline is produced per year. It is the parent compound for more
than 300 chemical products. A metabolite of aniline,
phenylhydroxylamine, is known to cause methemaglobinemis in exposed
workers . Although the mechanism is fairly well understood, it now
appears that some people are more susceptible to this condition than
others. The mechanism of this increased sensitivity needs further
investigation. The National Cancer Institute recently reported that
exposure to the maximum tolerated dose of aniline led to
hemangiosarcomas and other sarcomas of the 'spleen in rats, but not
in mice . Mutagen ic ity tests produced negative results except in the
presence of a comutagen. These findings indicate the need for
fur ther research, including carcinogenic studies, possibly on dogs .
There is no evidence indicating that aniline causes cancer in
humans, but further epidemiologic studies are required. There is
also a need to explore the mechanism by which aniline induces
splenic tumors in rats and to determine why it is not carcinogenic
in mice.
4,4 '-METHYLENE-BIS (2-CH=ROANILI=)
Studies in laboratory animals have demonstrated conclusively
that 4,4 '-methylene-bis {2-chloroaniline) (MOCA) is a carcinogen.
Such activity is expected because of the chemical's structural
similar ity to other carcinogenic aromatic amines. Widespread
11
environmental contamination by MOCA is attributed to one point source
in Adr fan, Michigan, thus increasing the need for epidemiologic
investigations of the exposed population. There is also a need to
study the metabolic fate of MOCA so that those who have been highly
exposed can be identified by these metabolic indicators and
prospective epidemiologic investigations can be facilitated.
Z. 4-DIAMINOTOLUENE
2,4-Diaminotoluene (2,4-DT) has been used in some hair dye
formulations. It is also used as an antioxidant and antiozonant in
some rubber products.
When administered orally, 2,4-DT is carcinogenic in rats and
mice, leading to liver and mammary gland tumors. This compound is
also a potent microbial mutagen, and induces mutations in Drosophila
melanogaster. There is no information on the mechanism by which
2, 4-DT is activated in susceptible species, including rats and mice.
Given the positive demonstration of carcinogenicity in two animal
spec ies and the da ta on the genotoxic ef feats of 2, 4-Dq in In vitro
systems, it is prudent to assume that humans may be under some
increased risk from exposure to 2,4-DT.
TRIFLURALIN
At the request of the Environmental Protection Agency, tl..=
report assesses only the potential mutagenic and genotoxic
12
properties of trifluralin, a widely used herbicide. During its
commercial preparation, an impurity, dipropylnitro~amine (NDPA), is
produced. Since NDPA is a mutagen, it is difficult to assess this
property in trifluralin. Mast mutagenicity studies of trifluralin
have produced negative results. Those that are positive for
chromo~omal damage and aneuploidy may be due to the presence of
NDPA. Parallel studies with NDPA have not been reported. NDPA-free
trifluralin and pure NDPA need to be tested, in tandem, for their
abilities to induce chromosomal damage and aneuploidy. mere is an
inadequate data base from which to evaluate the potential hazards of
tr if luralin and NDPA, to DNA and cell spindles in laboratory animals
or humans . Should HDPA be a germinal mutagen, exposures are
expected to occur at such low levels that its mutagenic potential
should be correspondingly low. Current manufacturing practice teas
considerably reduced the level of NDPA in trifluralin and its
formulations.
Positive mutagenicity test results obtained with trifluralin
have subsequently been attributed to a 177-ppm NDPA impurity
contained in the trifluralin rather than to the test chemical
itself. mere is a need for additional mutagenicity testing on
NDPA-free trifluralin for comparison with the existing studies.
Until these studies are performed, pure (NDPA-free) trifluralin
should not be considered mutagenic.
~3
F-CRESIDINE
E'-Cresidine is used almost exclusively as a chemical
intermediate in the manufacture of dyes. Other than a cancer
bioassay conducted by the National Cancer Institute, there is
virtually no other existing biologic data on this compound. Chronic
oral exposures to E:cresidine produced bladder cancer in both male
and female rats and mice as well as hepatocelluar carcinomas in male
rats and female mice. In a preliminary investigation, the compound
showed dose-response mutagenicity without metabolic activation in
the Salmonel la assay .
Because of the lack of data, it is difficult to evaluate the
potential health effects of this compound. Nonetheless, it must be
considered as a potential carcinogen in humans on the basis of the
carcinogenicity demonstrated in rats and mice. Me preliminary
mutagenicity data appear to show a positive response for
p-cresidine, but con f irmation is needed. Additional data are also
needed on metabolism, metabolic activation, mutagenicity, and
genetic toxicity in both animal and human In vitro test systems.
FURAZOLIDONE
Fur azolidone is one of the S-nitrofurans currently approved for
use as a systemic veterinary medicine in the United States, thereby
f inding its way into some edible tissues. It has also been used to
treat bacillary dysentery, typhoid, and other infectious diseases in
14
4.O ppb with current analytical methods. Various spectrophotometric
and thin layer chromatography procedures have-failed to yield
satisfactory and reproducible recoveries at these levels.
Furazolidine has exhibited carcinogenic effects in male and
female rats and mice just as other 5-nitrofurans have done. A
var iety of dif ferent tissues in each species have displayed these
effects. file compound is highly mutagenic in both microbial
(Escherichia coli) and insect (Drosophila melanogaster) test
systems, produces chromosomal damage (breakage, sister-chromatic
exchange, mitotic suppression) in human lymphocytes , and forms
interstrand cross-linking in bacterial (Vibrio cholera) DNA.
For the reasons discussed above, the use of furazolidone is now
being reviewed by the Food and Drug Administration. Resolution of
this matter awaits the development of a sufficiently sensitive and
reliable analytical method. Any identified problem most certainly
would be associated with the veterinary use of furazolidone. A
"solution" may involve the substitution of an efficacious product
known not to have the mutagenic and carcinogenic potential of
furazolidone .
RESEARCH RECOMMENDATI ONS
- The following recommendations have been excerpted from the
various chapters to highlight and focus attention on specific topics
the committee felt deserved further consideration.
15
Occurrence in the Environment
. . .
The anticipated changes in the use of fossil fuels, implicit in
the promotion of diesel engines and coal, may raise existing
environmental levels of some aromatic amines. Accordingly, it is
recommended that steps be taken to evaluate both the qualitative and
quantitative factors that attend these changes in practice.
General Analysis
Techniques must be developed to analyze for the presence of the
more volatile compounds such as aniline. Furthermore, methods must
be developed to determine the kinds and amounts of metabolites
present in persons exposed to these compounds.
Metabolism
Understanding of the metabolism of aromatic amines in laboratory
animals has advanced to the point that it can be extended to improve
the understanding of this process in humans. First it is necessary
to know which animal most closely approximates the metabol ic
responses of humans. Assuming that most chemical carcinogens need
to be metabolized in the host to active forms in order to exert a
carcinogenic effect, it becomes necessary to know how specific
carcinogens are activated in animals. If the metabolism of a
specific chemical carcinogen in human tissues is qualitatively
similiar to that observed in studies of tissues from a susceptible
16
test animal, then a potential carcinogenic effect might also be
observed in humans exposed to the chemical. Although the use of
humans for testing is dif f icult or impossible, it should be feasible
to make inferences based on in vitro tests with human cell lines,
mutagenicity testing with human liver S-9 fractions, and careful
mon itor ing of blood and ur ine of humans accidently exposed to
compounds of interest. It would be easier to assess the potential
risk to humans from many aromatic amines if additional biological
data on humans were obta ined.
Carcinogenic Potency and Risk Estimation
More attention needs to be focused on the concepts of initiation
and promotion and the inherent abilities of chemicals to act in one
or the other capacity as well as in both. Also, ways of predicting
carcinogen ic potency based on the present knowledge of the
mechanisms of carcinogenesis urgently need to be expanded. In the
absence of contrary evidence, aromatic amines which lack polar
groups should be regarded as carcinogens.
Epidemiology
Epidemiologic methodology needs to be improved so small
differences between exposed and control groups can be detected above
the background variability. One of the best ways to minimize this
variability is to conduct prospective follow-up studies so that the-
measure of exposure is at least as precise as possible. Of all the
17
compounds discussed in this report, the widespread exposure to
4, 4 ' -me thylene-bi s ~ 2-chloroan il ine ~ (MOCA) represents the best
oppor ton i ty f or th i s approach .
Aniline
Although there has been considerable research on aniline, there is
still much to be learned about its possible health effects. A compond
of such industrial importance deserves to be studied more thoroughly.
The hemangiosarcomas and sarcomas of the spleen and other organs
observed at the maximally tolerated dose (MTD) in the National Cancer
In s t i tu te b ioassay need to be examined fur ther in another 1 i fet ime
feeding study at three or four dose levels in a different strain of rat
to interpret the signif icance of previous observations.
A care inogen ic ity Study us ing Syr fan golden hamsters may also be
useful since these animals to develop bladder tumors after exposure to
other aromatic amines. In addition, a long term (preferably 8-10
years) dog-feeding study at the MTD should allay any suspicions
concerning the possible role of aniline in the causation of human
bladder cancer. The only test on dogs was conducted many years ago on
a few animals for too short a duration. Further studies on the
metabolites of aniline in urine should be directed toward explaining
the fa ilure of this compound to induce bladder cancer in dogs ~ if this
fa ilure is conf irmed) . Special attention should be pa id to
N-hydroxylated urinary metabolizes. Moreover, studies should be
conducted on its potential for teratogenicity and reproductive toxicity.
18
Epidemiological investigations on workers exposed to aniline
should also be undertaken. Monitoring of urine for aniline
metabolites to con f irm and quantitate exposures should be considered.
4, 4 ' -Me thyle ne-b i s (2-chloroan i 1 ine ) (MOCA)
Tnd ividuals exposed to MOCA in Adr fan, Michigan as a result of
faulty industr ial waste methods and others exposed to the compound
should be studied further to learn whether or not the compound is
carcinogenic in humans. First, the metabolic disposition of MOCA
should be explored so that methods for evaluating exposure can be
developed. Then these methods should be applied, to the population
at r isk, including an evaluation of necropsy specimens from any
member of this population who dies during the course of this
investigation . Such studies would clarify the potential r isk to
individuals, and aid in monitoring the effects of the cleanup
ef for ts . The f inal step is the prospective surve illance of this
population to determine whether exposure to MOCA increases their
tendency to develop cancer. In addition, studies on the potential
for teratogenicity and reproductive toxicity should be conducted.
2, 4-Diaminotoluene (2, 4-DT)
Recommendations for future research on 2, 4-DT include studies of
the mechanism by which the chemical is activated in rats, mice, and
humans, testing for carcinogenic) ty in other species to obtain more
data on the relationship between metabolism and carcinogenicity, and
19
examination of the In vitro metabolism of 2,4-DT in human tissues.
The resulting data would facilitate estimatation of risk to humans
exposed to 2, 4-DT. Studies on the potential for teratogenicity and
reproduct ive tax ici ty should also be conducted .
Tr i f luralin
Tandem mutagenicity studies on pure trifluralin and its
contaminant, N-nitrosodipropylamine should be conducted to determine
which compound is responsible for chromosomal damage and aneuploidy
noted in previous studies.
p-Cresidine
In vitro studies of human tissues and tests with animals should
be conducted to gather data on the metabolism, metabolic activation,
mutagenicity, and genetic toxicity of p-cresidine. Furthermore,
studies on the potential for teratogenicity and reproductive
toxicity need to be performed.
Furazolidone
A sufficiently sensitive and reliable analytical method for
fura 201 idone is needed. Moreover, studies on that compound's
potential for teratogenicity and reproductive toxicity should be
conducted.
20
Re ferences
Bengtsson , U., L. Angervall , H. Ekman, and L. Lehman . 1968.
Transitional cell tumours of the renal pelvis in analgesic
abusers. Scand. J. Urol. Nephrol . 2 :145-150.
Case, R.A.M., M.E. Hosker, D.B. McDonald, and J.T. Pearson. 1954.
Tumours of the urinary bladder in workmen engaged in the
manufacture and use of certa in dyestuf f intermediates in the
British chemical industry. Part I: file role of aniline,
benz id ine, alpha-naphthylamine and beta-naphthylamine . Br . J.
Ind . Hed . 11: 7 5-104 .
Clayson, D.B., and R.C. Garner. 1976. Carcinogenic aromatic amines
and related compounds. Pp. 366-461 in C.E. Searle, ed. Chemical
Carcinogens. ACS Monograph 173. American Chemical Society,
Washington, D.C.
Hueper, W.C. 1942 . Occupational Tumors and Allied Diseases. Thomas,
Springf ield, Ill .
Melick, W.~., H.M. Escue, J.J. Naryka, R.A. Mezera, and E.P. Wheeler.
1955. m e first reported cases of human bladder tumors due to a
new carcinogen--xenylamine. J. Urol. 74:760-766.
Melick, W.F., H.M. Escue, J.J. Naryka, and R.E. Kelly. 1971.
Bladder cancer due to exposure to para-aminobiphenyl: A 17-year
followup. J . Urol. 106: 220-226 .
21
Miller, E.C., and J.A. Miller. 1976. me metabo' ism of chemical
carcinogens to reactive electrophiles and their possible
mechanisms of action in carcinogenesis. Pp. 737-762 in C.E.
Searle, ed. Chemical Carcinogens. ACS Monograph 173. American
Chemical Society, Washington, D.C.
National Academy of Sciences . 1981. Health Ef feats of Exposure
to Diesel Exhaust . Repor t of the Health Ef feats Panel . Diesel
Impacts Study Committee. National Research Council, Washington,
D.C. 197 pp.
Rathert, P., H. Melchior, and W. Lutzeyer. 197S. Phenacetin: A
carcinogen for the ur inary tract. J. Urol. 113: 653-657.
Rehn, L. 1895. Ueber Blasentumoren be i Fuchsinarbeitern . Arch.
Klin. Chir. 50: 588-600.
Shriner, C.R., J.S. Drury, A.S. Hammons, L.E. Towill, E.B. Lewis,
and D.M. Opresko. 1978. Reviews of the environmental effects of
pollutants: II. Benzidine. Information Center Complex,
Information Division, Oak Ridge National Laboratory, prepared for
Health Effects Research Laboratory, Office of Research and
Development, U. S. Environmental Protection Agency, Cincinnati,
Ohio, EPA-600/1-78-024, 139 pp.
22
