Information on Chemical Carcinogens

1. Introduction bladder cancer in rubber workers. Asbestos dust,

on the other hand, will present health problems for
Chemical carcinogens are agents that are capable many years, though hopefully on a much smaller
of inducing cancer in humans or animals. Most of scale than when exposure to the most hazardous
the many hundreds of chemical carcinogens forms was very much greater.
known have been recognised as such as a result of
tests in rats or mice. A relatively small number are Occupational causes of cancer have been much
occupational carcinogens, having been found to simpler to identify when there has been a greatly
cause cancer in persons exposed to them in the increased risk of workers developing a particular
workplace. Sometimes occupational cancer has form of cancer, or when the cancer caused has
arisen from materials where the actual causative been one that is very uncommon in the general
agent remains unknown. Some chemicals used as population. For example, past conditions in those
drugs are also known to have caused human parts of the chemical industry using certain
cancer. aromatic amines led to a 30-fold increased risk of
workers developing bladder cancer. Mesothelioma
Many lists of human carcinogens have been of the pleura and peritoneum, and
published, and differ widely according to the haemangiosarcoma of the liver, are normally very
strength of the evidence that is accepted. It should rare forms of cancer but have arisen in workers
not be assumed that carcinogens recognised only exposed to asbestos dust and vinyl chloride
experimentally are necessarily less hazardous than respectively. The limitations of epidemiology are
accepted occupational carcinogens that happen to such, however, that it is very difficult to identify a
have been encountered in industrial processes, cause of cancer where the cancer is one already
often under working conditions now regarded as common in the general population (especially lung
extremely poor. cancer), and where the proportional increase in
risk is not very large.
Chemical carcinogenesis is a prolonged process
with many stages, mostly very imperfectly Because of the long time-lag in chemical
understood, and a variety of other factors are carcinogenesis, it is particularly important to avoid
known which potentiate or inhibit the exposure of young persons to potential
development of cancer. Occupational cancer has carcinogenic agents. Special care is also needed to
commonly taken 20 or more years from first avoid exposure to carcinogens and other harmful
exposure to become apparent, and this time-lag chemicals of women who are pregnant, or may
contributes to the difficulties experienced in become pregnant. This is because the foetus is at
linking cause and effect. Nevertheless, high risk from harmful chemicals ingested by the
identification of carcinogenic factors, coupled with mother.
changes in industrial practices and various
legislative measures, have resulted in the virtual This document is particularly concerned with the
elimination of some former occupational cancers. many different types of chemical carcinogens,
Examples are cancer of the scrotum in chimney their potency as carcinogens, the wide differences
sweeps, cotton-spinners and tar workers, and in their biological effects, and other factors

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influencing their risks of actually causing cancer. Chemical carcinogens similarly vary very greatly
However, concern over possible carcinogenic risks in potency. Recently much work has been done to
must not deflect attention from the very many express carcinogenic potency quantitatively as the
much shorter-term risks from chemicals. Apart daily dose that will result in cancer in 50% of test
from fire and explosion hazards, there are the animals in long-term experiments (18 or 24
many forms of toxic action that can rapidly cause months, most of the life-span of a rat or mouse).
death or serious injury. Chemicals must always be Based on past tests judged sufficiently
handled responsibly, not only with due regard for trustworthy, these show that carcinogenic
known hazards but also, especially in research, for potencies range over some 6-7 orders of
the unexpected. A recent tragic example of this magnitude, from aflatoxin B1, carcinogenic for rats
was the rapid development of irreversible brain at only 1 μg per kg body-weight per day, to
damage from a relatively simple pyridine compounds with barely detectable activity at 1 g
derivative (MPTP) formed during illicit drug per kg per day. Many of the most important
synthesis. carcinogens fall around the middle of this range.
There is no clear dividing line between very weak
2. Types of Chemical Carcinogen carcinogens and completely inactive substances.

Many, but not all, known chemical carcinogens Obviously, carcinogenic potency is an important
fall into some fairly well-defined chemical classes, factor to be considered in assessing to what extent
such as polycyclic aromatic hydrocarbons (PAHs), a chemical reported carcinogenic is likely to be
aromatic animes and nitro compounds, alkylating hazardous to health. It is not, however, the only
agents and N-nitroso amines and amides. The N- factor. Since a chemical has to enter the body in
nitroso compounds do not include any accepted order to elicit carcinogenic or other toxic effects,
occupational carcinogens, but are outstanding in account also has to be taken of volatility or
that most of the several hundred tested are potent dustiness, which may lead to the substance being
experimental carcinogens. In the inorganic field, inhaled, and of course to the scale of its use. Some
human cancers have been caused by occupational chemicals are much more readily absorbed
exposure to largely uncertain compounds of through the skin than others.
nickel, chromium and arsenic, and especially to
asbestos dust. 4. Mechanisms of carcinogenic action

3. Carcinogenic potency The basic biological action of a chemical leading

to cancer is thought to be an attack on DNA, the
The basic principle of toxicology, that it is the basic genetic material of the cell, to produce a
dose that makes the poison, was laid down over change that is not repaired by the body's DNA-
400 years ago. Substances regarded as entirely repair mechanisms, and which is then passed from
innocuous will still be harmful in very large cell to cell during division. Such heritable changes
amounts, while highly toxic substances will not be are known as 'mutations'. Alkylating agents
harmful in sufficiently small amounts. interact directly with DNA and other
Carcinogens are unusual in toxicology terms in macromolecules, but most carcinogens (PAHs,
that the effects of exposure are cumulative. aromatic amines, etc.) do not do so until they have

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undergone one or more metabolic changes to yield 5. Carcinogenic chemicals
an 'ultimate carcinogen'.
As already indicated, there are very great
Many chemicals other than known carcinogens differences between chemical carcinogens in their
have long been known to induce mutations in carcinogenic potency, mechanisms of action and
living materials, i.e., are 'mutagens'. Recognition other factors influencing the extent to which they
of the importance of metabolism of carcinogens to may pose a carcinogenic risk. In the lists which
active agents suggested a close relationship follow, indications of possible risks are given,
between mutagens and carcinogens, and is the based on the system of 1 to 3 stars as used at the
basis of many short-term tests (particularly the University of Birmingham in its earlier
Ames bacterial test) being used as indicator of information and rules for chemical carcinogen use
chemicals that may also be carcinogenic. (1980). As then, the gradings are necessarily very
Substances active in such tests are termed subjective and based on current knowledge, but do
'genotoxic'. attempt to allow for factors such as volatility or
persistence in the body as well as carcinogenic
Some substances found to be carcinogenic, potency. It cannot allow, of course, for the scale
however, do not show genotoxic activity, and and frequency of any intended use.
these are referred to as 'epigenetic' or 'non-
genotoxic'. This ill-defined class includes tumour The letter H is used to show a RECOGNISED
promoters, co-carcinogens, some hormones and human carcinogen, usually occupational but also
immune-suppressants, which in various ways including some anti-cancer drugs. Chemicals
magnify or accelerate carcinogenicity by other without an H, particularly many N-nitroso
agents, including viruses. For non-genotoxic compounds, may well pose greater carcinogenic
carcinogens there may well be a threshold dose risks in practice than many accepted human
level below which there is no risk of any carcinogens. It is again emphasised that, even for
carcinogenic action. For genotoxic carcinogens, on many undoubted carcinogens, the principal risks
the other hand, dose-response relationships have of exposure often derive from their much shorter-
failed to show the existence of a threshold level term toxic actions.
though, as with toxic agents, there must be some
level below which risks become negligible. *** High carcinogenic hazard
** Significant carcinogenic hazard
The value of a battery of short-term tests is
* Carcinogenicity established, but little hazard
increasingly seen as revealing mechanisms of
with reasonable care
biological action, rather than as simply indicating
No mark Carcinogenicity weak or possible
possibilities of carcinogenicity. Information on
metabolic processes is also important, particularly H Known to have caused cancer in humans
with regard to differences in metabolism between
experimental animals and man. Better 5.1 Aromatic amines
understanding of this type indicates that some 2- (or α-) Naphthylamine, 4-aminobiphenyl and
weakly carcinogenic agents of industrial benzidine (4,4'-diaminobiphenyl) are established
importance are very unlikely to pose any causes of bladder cancer in industrial workers.
significant risks of carcinogenesis in practice. Some related 2- and 3-ring aromatic amines are

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also carcinogenic. Some activity has been detected *** 4,4'-dinitrobiphenyl
in some single-ring amines. ** 2-nitronaphthalene
** 2-nitrofluorene
Benzidine has had many uses in analytical
chemistry and safer alternatives should be used. ** many substituted 2-nitrofurans
3,3' ,5,5'-Tetramethylbenzidine and 3,3' ,4,4'-tetra- ** 4-nitroquinoline 1-oxide and related
aminobiphenyl (diaminobenzidine) are free of compounds
significant activity, but o-tolidine and 3-amino- 9- * nitro derivatives of polycyclic aromatic
ethylcarbazole are carcinogenic. The hydrocarbons
carcinogenicity of 1-naphthylamine appears to
be entirely due to contamination with 2- 5.3 Dyes
naphthylamine.
A number of azo and other dyes are carcinogenic
for experimental animals. Methyl or methoxy
H*** 2-naphthylamine
groups can markedly increase activity. Many
H 1-naphthylamine commercial dyes are of very low purity.
H*** 4-aminobiphenyl
* 4-dimethylaminoazobenzene (butter or
H*** benzidine
methyl yellow) (diethyl homologue is
** o-tolidine inactive)
** 3,3'-dichlorobenzidine * o-aminoazotoluene
* 3,3'-dimethoxybenzidine (o-dianisidine) chrysoidines (2,4-diaminoazobenzenes;
4,4'-methylenedianiline methyl derivates more mutagenic and
possibly more carcinogenic)
* 4,4'-methylenebis (2-chloroaniline)
?H auramine (some bladder cancer cases in
*** 2-aminofluorene
manufacturing workers; this and weak
*** 2-acetamidofluorene activity of commercial dye possibly due to
Michler's ketone)
** 4-aminostilbene
magenta (some bladder cancer cases in
** 3-amino-9-ethylcarbazole
manufacturing workers, but no evidence that
* quinoline dye itself is carcinogenic)
* diphenylamine (if contaminated with 4-
aminobiphenyl) 5.4 Alkylating agents
aniline (main risks from toxicity) These interact directly (i.e. without prior
ethidium bromide (carcinogenicity metabolism) with biological materials and
unknown, but is a potent mutagen) commonly have irritant, toxic, mutagenic and
carcinogenic actions. They include chemicals of
5.2 Aromatic nitro compounds major industrial importance, and also various
Those corresponding to carcinogenic aromatic drugs used in cancer treatment. Mustard gas and
amines should be assumed to be carcinogenic. bis(chloromethyl) ether (BCME) have caused
occupational lung cancer, while human cancer has
*** 4-nitrobiphenyl also occurred in some patients treated with
alkylating agent drugs. Any reactive alkylating

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agent should be assumed to be potentially ** 2,3-dibromopropan-1-ol
carcinogenic in addition to its other hazards. bromomethane (methyl bromide)
iodomethane (methyl iodide)
BCME may arise unintentionally from interaction
?H* benzotrichloride
of formaldehyde with hydrogen chloride. Amounts
formed in air appear to be generally very small, ** β-propiolactone
but high levels have been detected from Friedel- * propane sultone
Craft mixtures containing formaldehyde, and ?H some aziridines (ethyleneimines)
commercial chloralkylation may have led to some
?H* ethylene oxide
lung cancer cases.
other epoxides where ring is unstable

Methylation with diazomethane is known to be

5.5 Other organic halides, etc
hazardous. Also its precursors methylnitrosourea,
N-methyl-N'-nitroso-N-nitro-guanidine (MNNG) Compounds with a very stable carbon-halogen
and especially methylnitrosourethane are potent bond may still be metabolished to a carcinogenic
carcinogens (see Section 6), though methyl- species, including vinyl chloride which led to liver
nitroso-o-toluenesulphonamide is not. The blood-vessel cancer in heavily-exposed workers.
methylating agent methyl fluorosulphonate Various polyhalogenated chemicals are of
('magic methyl') has been reported to cause rapid considerable concern because of their persistence
death after a relatively small laboratory spillage; in the environment and the body, toxic effects and
for such substances possible carcinogenic risks are association with highly toxic polychlorinated
hardly relevant. dibenzodioxins and dibenzofurans; relatively little
is known about the carcinogenic risk. For
H*** bis(2-chloroethyl) sulphide (mustard gas) halogenated solvents, see section F.
H*** bis(chloromethyl) ether (BCME)
H* chloroethene (vinyl chloride)
*** chloromethyl methyl ether (normally
contains some BCME) * chloroprene

H*** various nitrogen mustard derivatives H** cyclophosphamide

** alkyl methanesulphonates polychlorinated biphenyls (PCBs)

** dimethyl sulphate polybrominated biphenyls (PBBs)

*** methyl fluorosulphonate (very high toxicity - some polychlorinated pesticides

see above)
5.6 N-Nitroso compounds and hydrazines
*** diazomethane and certain precursors (see
above) A very high proportion of nitrosamines
** dimethylcarbam(o)yl chloride (RR'N.NO) tested are potent experimental
carcinogens, with a very wide range of body
* triethylene phosphoramide (TEPA)
organs being affected. The initial discovery
* triethylene thiophosphoramide (thio TEPA)
resulted from the occurrence of severe liver
** tris(2,3-dibromopropyl) phosophate (former poisoning from the use of N-nitrosodimethylamine
clothing flameproofer) as a solvent by laboratory workers. Risks from
** 2,3-dibromo-1-chloropropane (has caused many are increased by their volatile nature.
sterility in males)

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Related carcinogens include alkylnitrosamides Benzo(a)pyrene is among the complex mixtures of
(e.g. methylnitrosourea), 1,2-dialkylhydrazines, such compounds formed during incomplete
diazoalkanes, and guanidines such as the strong combustion of organic matter, held responsible for
mutagen MNNG. Involvement of some N-nitroso occupational scrotal and skin cancer in workers in
compounds in some human cancers is strongly contact with soots, tars and mineral oils. Their role
suspected but not firmly established. in other forms of human cancer is uncertain, but
they may well be one of the factors in lung cancer
*** N-nitrosodimethylamine caused by smoking.
(dimethylnitrosamine)
*** N-nitrosodiethylamine (diethylnitrosamine) Use of the pure compounds outside cancer
research is (or should be) very limited, but they
** most other compounds RR　N.NO, with
some exceptions (N-nitrosodiphenylamine, require particular care in handling owing to their
and those with a tert-butyl group) potency and likely persistence within the body.

* N-nitrosodiethanolamine (found in
*** benzo(a)pyrene
engineering oils bases on ethanolamines
with nitrite inhibitor) *** 7,12-dimethylbenz(a)anthracene

** N-nitrosopiperidine *** 3-methylcholanthrene

** N-nitrosopiperazine *** dibenz(a,h)anthracene

** N-nitrosomorpholine H* cutting oils, lubricants, tars, soots etc., when

contaminated with agents of this type.
* N-alkyl-N-nitrosoureas, H2N.CO.N(NO)R,
also N-nitroso di- and tri-alkylureas
5.8 Naturally occurring carcinogens
*** N-alkyl-N-nitrosourethanes (powerful local
carcinogens) A variety of plants and micro-organisms produce
carcinogenic metabolites. Having complex
** N-alkyl-N'-nitro-N-nitrosoguanidines (e.g.
MNNG)
structures they are not very volatile, but some are
highly potent and may represent considerable
** 1,2-dialkylhydrazines, RNH.NHR'
hazards if handled as isolated chemicals.
* procarbazine (drug; substituted 1,2- Aflatoxins, metabolites of a fungus contaminating
dimethylhydrazine) foodstuffs, may have contributed to the high level
** azoalkanes, R.N-N.R' of liver cancer in parts of tropical Africa. Dusts
** azoxyalkanes, R.NO-N.R; encountered in the woodworking and leather
industries have caused cancer of the nasal sinuses
* methylazoxymethanol
in workers, but the agents responsible are not
* 1-phenyl-3,3-dimethyltriazene and known.
analogues
?H** aflatoxin B1 and less active analogues (from
5.7 Polycyclic aromatic hydrocarbons and an Aspergillus)
heterocycles
* sterigmatocystin (from an Aspergillus)
Many such compounds containing 4 to 6 aromatic
* griseofulvin (from a Penicillium)
rings are potent carcinogens, their risks being
* streptozotocin (methylnitrosourea glucoside;
increased by their likely persistence in the body.
from a Streptomyces)

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* cycasin (methylazoxymethanol glucoside; H*** asbestos dust
from Cycads) (major occupational health hazard, having
led to cancer of lung, particularly in
* patulin (carcinogenic on injection but not
smokers, mesothelioma of the pleura and
orally)
peritoneum, and crippling fibrous
* bracken fern (complex toxic and degeneration of the lung. Uses and handling
carcinogenic metabolites) subject to strict legislative controls.
** phorbol esters (potent tumour-promoting and
co-carcinogenic constituents)
6. Toxicity and carcinogenicity of some
H* dusts from certain hardwoods solvents and other compounds

5.9 Inorganic carcinogenic agents Many solvents are used in particularly large
quantities, and the volatility of many contributes to
Various processes involving mining, refining and
the possibilities of excessive exposure. They vary
uses of some metals, particularly nickel and
very greatly in their toxicity, some show
chromium, have been associated with occupational
carcinogenicity in animals, and benzene is an
cancers of the respiratory tract. Exposures to dusts
accepted occupational carcinogen for humans.
and fumes have been complex, and are of
Some (1,1,1-trichloroethane, tetrachloromethane)
uncertain relevance to work under laboratory
may be phased out to help control ozone layer
conditions, where toxic hazards are probably much
depletion.
more important.
H** Benzene
H* nickel
This highly toxic bone-marrow poison can
(dusts and fumes have caused lung and nasal
cause severe or fatal anaemia. Accepted
sinus cancers in workers. Various
cause of leukaemia from high exposure of
compounds, possibly only sparingly soluble
workers in various occupations. Toluene and
ones, are carcinogenic in animals,
other alkylbenzenes are detoxified by
particularly nickel subsulphide Ni3S2 but
metabolism of the alkyl group(s); they are
not amorphous NiS)
correspondingly less toxic, with no
H* chromium suspicions of carcinogenic risk.
(human and experimental lung carcinogen;
Dichloromethane (methylene chloride)
apparently Cr(VI) compounds only)
Some evidence for weak carcinogenicity of
H* beryllium borderline significance only.
(human and experimental lung carcinogen)
Trichloromethane (chloroform)
?H cadmium Toxicity high; has given slight evidence for
(dubious evidence for small increase in risk experimental carcinogenicity.
of prostate cancer)
?H* Tetrachloromethane (carbon
H* arsenic
tetrachloride)
(inorganic compounds carcinogenic for
Toxicity high. Experimental liver
human skin and lung in former medicinal
carcinogen, suspected in having caused liver
and agricultural uses)
cancer in a few heavily exposed workers.

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 Bromomethane (methyl bromide) Dimethyl sulphoxide (DMSO)
Fumigant use has caused toxic effects and No reason to suspect carcinogenicity, but
some deaths. Some experimental evidence may facilitate entry of more harmful
for carcinogenic action. substances into the body.

Trichloroethylene *** Hexamethylphosphoramide

Readily breaks down to more toxic agents in (hexametapol) (HMPA)
absence of an inhibitor. Very weak Inhalation at extremely low levels has
experimental carcinogen, by mechanisms not induced nasal cancer in rats. The mechanism
applicable to humans. of this may not be directly relevant to man,
but pending further knowledge it must be
Tetrachloroethylene (perchloroethylene)
assumed to be a significant carcinogenic
Evidence for weak carcinogenicity of
hazard for man also.
borderline significance only.
Formaldehyde and formalin
1,2-Dichloroethane (ethylene dichloride)
Highly irritant and toxic. Inhalation at levels
Has caused many cases of acute poisoning.
causing significant tissue damage causes
Some evidence for experimental
cancer in nasal sinuses of rats. To date no
carcinogenicity.
reliable evidence that extensive occupational
** 1,2-Dibromoethane (ethylene dibromide) exposure has caused human cancer.
Toxicity high, and is a potent experimental
Glutaraldehyde
carcinogen, leading to increasing restrictions
Highly irritant and toxic. No evidence to
on its commercial use.
date for carcinogenicity.
1,1,1-Trichloroethane (methyl
* Butadiene
chloroform)
Clearly carcinogenic for rats and mice
No evidence for any carcinogenicity, but has
inhaling high levels of the gas. No evidence
caused fatalities through high industrial
that large-scale industrial use has been
exposure and solvent abuse.
carcinogenic for humans.
1,2-Dichlorobenzene (o-dichlorobenzene)
* Acrylamide
Carcinogenicity tests have been negative.
Toxicity high, including by skin contact.
isoPropanol Accepted neurotoxin, with evidence
Former 'strong-acid' process of manufacture accumulating that it may cause testicular
caused cases of nasal sinus cancer in damage and genetic effects. A weak
workers. No evidence that solvent itself is experimental carcinogen.
carcinogenic.
?H* Acrylonitrile
1,4-Dioxane High toxicity for nervous system, with
High exposures have caused deaths in effects similar to cyanide. Some suspicions
workers. High dosage to rats and mice in of possible occupational carcinogenesis.
drinking water were carcinogenic, but there
* Ethyl carbamate (urethane)
is no human evidence for carcinogenicity.
Experimental carcinogen, but most tests
Dimethylformamide required presence of a tumour promoter also.
Heavy occupational exposure has given rise
to suspicions of testicular damage and
cancer.

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7. Epidemiological Surveys of chemists deaths in Britain and the USA, largely but not
entirely those from lung cancer. A high, but much
Two studies of the mortality of chemists (USA, more uncertain, proportion of cancers is attributed
1969; Sweden, 1976) indicated that some causes to various unsatisfactory aspects of diet. Much
of death were less common in chemists than in the heart disease, as well as other diseases
general population, but that there was an increased characteristic of the 'western' way of life, are also
risk of death from lymphoma (cancer of the attributed in large measure to smoking or dietary
lymphoid system). In Britain the Royal Society of factors.
Chemistry studied mortality data from 1965-1989
and the results showed overall low mortality rate Many serious diseases, once accepted as
but with an excess mortality from lymphatic and inevitable, are thus now regarded as having
haematopoietic cancers, in particular leukaemias. definite causes and as being capable of prevention.
For a detailed study of the causes of cancer (in the
Development of lymphoma, probably a virally- USA but very relevant to Britain also), the now
induced form of cancer, can be an unfortunate classic analysis is by the British epidemiologists R
consequence of treating transplant patients with Doll and R Peto ('The Causes of Cancer:
drugs to suppress their immune system. It seems quantitative estimates of avoidable risks of cancer
possible that heavy exposure to some as yet in the United States today' Oxford University
unidentified chemicals in the workplace might Press, 1981). At the more popular level, P
similarly have an immunosuppressive action, Goodwin's 'Can you Avoid Cancer?' (British
which could then trigger development of Broadcasting Corporation, 1984) can be strongly
lymphoma in some people. While this at present is recommended.
speculative, it emphasises the desirability of
avoiding excessive exposure to chemicals in The following brief bibliography may also be
general, not simply those already recognised as useful:
having toxic or carcinogenic actions.
Alderson, M (1986) Occupational Cancer.
Butterworths, London
8. Causes of cancer

Richardson, ML, Ed. (1986) Toxic Hazards

The proportion of cancers resulting from
Assessment of Chemicals. Royal Society of
occupational carcinogenesis has been
Chemistry, London
controversial, but has generally been put at around
5% of the total incidence. Such estimates reflect
Searle, CE, Teale, OJ (1988) Introduction to
working conditions of some two decades earlier.
Carcinogen Hazards: an outline of chemical
With greater knowledge and improvements in
carcinogens, hazards and test methods, with data
working conditions in countries such as Britain,
and assessments on 78 miscellaneous chemicals.
the proportion of cancer attributable to working
Cancer Research Campaign, London.
conditions will hopefully be less and decreasing
with time.
Searle, CE, Teale, OJ (1990) Occupational
Carcinogens. In Chemical Carcinogenesis and
Smoking (and other ways of using tobacco) are
Mutagenesis I, ed. CS Cooper, PL Grover,
now held responsible for one third of all cancer
Handbook Exp. Pharmacol, 94(l), 103-151

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 Williams, GM, Weisburger, JH (1986) Chemical
Vessey, MP, Gray, M, Eds (1985) Cancer Risks Carcinogens. In Casarett and Doull's Toxicology:
and Prevention. Oxford University Press, Oxford. the Basic Science of Poisons, 3rd edn. 99-173.
Eds. CD Klaassen, MO Amdur, J Doull.
Macmillan, New York.

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