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Website: www.chem-tox-ecotox.org, Published: June 2017
SCIENTIFIC REVIEWS
Environmental Carcinogenic Substances, Exposure and Risk Assessment
for Carcinogenci Potential. Classifications and Regulations by
International and National Institutions
Athanasios Valavanidis
Department of Chemistry, National and Kapodistrian University of Athens, University
Campus Zografou, 15784Athens, Greece
E-mail: valavanidis@chem.uoa.gr
ABSTRACT
Carcinogens are chemical substances, mixtures, natural products, physical agents (sunlight,
radioactivity, etc), industrial products and occupations that have different levels of cancer-
causing potential. The majority of carcinogens are of environmental origin and most of them
can cause cancer after prolonged and high levels of exposure. The first environmental
carcinogens were connected with various occupations where workers were exposed during
their working lives (such as asbestos, benzene, leather products, etc). A great number of
carcinogens were identified in the last century, such as tobacco smoke, urban air suspended
particulates and industriual products (polychlorinated pesticides, polychlorinated biphenyls,
vinyl chloride, etc). A number oif carcinogens of natural origin were discovered in various
foods, such as tannic acid, safrole, pyperadine and alpha-methylpyrroline in black pepper,
aflatoxins and ochratoxin A made by fungal food contaminants. Cooking and frying produce
carcinogenic heterocyclic amines in cooked meats and some highly mutagenic compounds
such as polycyclic aromatic hyudrocarbon.
Cancer is a disease characterised by “damaged” or mutations of cellular DNA and
uncontrolled growth of altered cells into neoplastic tumours. This review explains in simple
terms the present knowledge on carcinogenic substances and factors, the methodology for
their classification by international and national scientific organizations, the mechanisms of
carcinogenic potential. The review presents the most important causes of cancer and the
regulations for the protection of workers, consumers from carcinogenic exposure and the
environmental problems from chemical pollutants with hazardous carcinogenic properties.
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Introduction: What Are Carcinogens?
Chemical substances, mixtures, physical factors (sunlight, radioactivity, etc)
and prolonged exposures that can lead to develop human cancer are called in
general carcinogens. Experimental evidence showed that exposure to carcinogens do
not cause cancer in every case, all the time. Substances labeled as carcinogens may
have different levels of cancer-causing potential. Some may cause cancer only after
prolonged and high levels of exposure. And for any particular person, the risk of
developing cancer depends on many factors, including how they are exposed to a
carcinogen, the length and intensity of the exposure, and the person's genetic
makeup.1-4
Cancer is a disease characterised by “damaged” or mutations of cellular DNA
and uncontrolled growth of altered cells and their ability to migrate from the original
site and spread to different parts of the body. A mutation means a permanent
change in the amount or structure of the genetic material in a cell. Mutagen is used
for agents increasing the occurrence of mutations. Many mutagenic substances are
also carcinogenic, but not all.5,6
Figure 1. The majority of the known carcinogens have been identified and protective
measures or restrictions in their use have been implemented in industrial countries.
Most asbestos products have been banned from the 1990s (in EU from 2005)
International Ban Asbestos Secretariat [http://ibasecretariat.org/asbestos_ban_list.php].
Scientists use the combination of data from cultured cells (in vitro),
experimental animals (in vivo) and epidemiological studies, to make an educated
assessment of a substance's cancer-causing ability. When the evidence is conclusive,
the substance is labeled as a carcinogen. When the available evidence is compelling
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but not conclusive, the substance may be considered to be a probable carcinogen.
But in some cases there simply isn't enough information to be certain one way or the
other. Carcinogens do not cause cancer at all times, under all circumstances. Some
may only be carcinogenic if a person is exposed in a certain way (for example,
swallowing it as opposed to touching it). Some may only cause cancer in people who
have a certain genetic makeup. Some of these agents may lead to cancer after only a
very small exposure, while others might require intense exposure over many years.7
Even if a substance or exposure is known or suspected to cause cancer, this
does not necessarily mean that it can or should be avoided at all costs. For example,
estrogen is a known carcinogen that occurs naturally in the body. Exposure to
ultraviolet (UV) radiation from sunlight is also known to cause cancer, but it’s not
practical (or advisable) to completely avoid the sun. These lists also include many
commonly used medicines, particularly some hormones and drugs used to treat
cancer. For example, tamoxifen increases the risk of certain kinds of uterine cancer
but can be very useful in treating some breast cancer. Lifestyle factors are
considered now as the most important carcinogens (tobacco smoke, alcohol, diet of
salty and smoked–cured meat, lack of vegetables and fruit in diet, obesity and lack of
exercise). But also, other factors which increase the risk for cancer are age (over 65),
gender, family history, sexual behaviour, infectious agents (viruses, etc). The type of
carcinogenic substance (cancer potential and mechanisms of initiation and
progerssiosn) and the extent of exposure also play a role. 8
International and National Agencies for the Classification of
Carcinogens
Several national and international agencies are responsible for determining
the cancer-causing potential of different substances. The most important is the
International Agency for Research on Cancer (IARC, Lyon, France) which is part of
the World Health Organization (WHO) of the United Nations and its main role is to
identify causes of cancer by using the scientific evidence from worldwide scientific
publications and research projects. Also, the most widely used system for classifying
carcinogens comes from the IARC. In the past 30 years, the IARC has evaluated the
cancer-causing potential of more than 900 likely candidates (chemicals, materials,
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occupations, factors), placing them into one of the following groups: Group 1
(carcinogenic to humans), Group 2A (probably carcinogenic to humans), Group 2B
(“possibly carcinogenic to humans”), Group 3 (“unclassifiable as to carcinogenicity in
humans”), and Group 4 (“probably not carcinogenic to humans”). At present in
group 1 there are approximatelly over 100 chemicals and factors classified as
“carcinogenic to humans.” 9,12
The National Toxicology Program (NTP) is formed from parts of several
different US government agencies, including the National Institutes of Health (NIH),
the Centers for Disease Control and Prevention (CDC), and the Food and Drug
Administration (FDA). The NTP updates its Report on Carcinogens (RoC) every few
years. The Report on Carcinogens identifies 2 groups of agents: a. known to be
human carcinogens, and b. reasonably anticipated to be human carcinogens. The
current version of the RoC lists about 250 substances and exposures. The RoC does
not list substances that have been studied and found not to be carcinogens.13-15
The US Environmental Protection Agency (EPA) maintains the Integrated Risk
Information System (IRIS), an electronic database that contains information on
human health effects from exposure to certain substances in the environment. The
EPA uses a rating system similar to that of IARC when describing the cancer-causing
potential of a substance: Group A (carcinogenic to humans), Group B (likely to be
carcinogenic to humans), Group C (suggestive evidence of carcinogenic potential),
Group D (inadequate information to assess carcinogenic potential), Group E (not
likely to be carcinogenic to humans).16-18
Other U.S. federal agencies, such as the CDC’s National Institute for
Occupational Safety and Health (NIOSH), the Food and Drug Administration (FDA),
the American Conference of Governmental Industrial Hygiensists (ACGIH) and the
National Cancer Institute (NCI) may comment on whether a substance or exposure
may cause cancer and/or what levels of exposure to a particular substance might be
considered acceptable. Some state agencies also keep lists of known or probable
carcinogens. Regulations of chemical hazards and carcinogens in the working
environment are managed by governmental authorities in Scandinavian countries,
such as the Chemicals Inspectorate and the Swedish National Board of Occupational
Safety and Health .19,20
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Figure 2. International Agency for Research on Cancer (IARC) headquartered in Lyon,
France, operates under the auspices of the WHO. International groups of scientists
evaluate yearly the weight of the evidence that an agent, chemical compound,
complex mixtures (includin foods), occupational exposures, physical and biological
agents and lifestyle factors, can influence the risk of cancer in humans
Regulation for Carcinogenic Substances in the European Union and
Other Countries
The European Economic Community (EEC) introduced a European law covering
dangerous substances in 1967 (67/548/EEC) to protect public health, environment,
and especially workers handling dangerous substances (with a list of 8.000
chemicals). It was known as the Directive on Dangerous Substances with provision
for approximation of laws and regulations on the classification, packaging and
labelling of dangerous substances (followed by many technical changes, with the 31st
technical adaptation in 2009). The carcinogens were regulated by the document
“Setting of Specific Concentration Limits for Carcinogens (in Annex I of Directive
67/548/EEC) Guidelines for inclusion of potency considerations” that gave guidance
as to how potency considerations may be included in the setting of specific
concentration limits for carcinogens in the working environment and other
environmental compartments.
The European Agency for Safety and Health at Work Directive introduced the
2004/37/EC directive – “carcinogens or mutagens at work” for the protection of workers
from the risks related to exposure to carcinogens or mutagens at work (6th individual
Directive within the meaning of Article 16(1) Directive 89/391/EEC). This Directive
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replaced Directive 90/394/EEC and its subsequent amendments (Directive 97/42/EC
and Directive 1999/38/EC).
In 2016 the European Commission proposed to amend the European Union
directive on workplace safety by modifying occupational exposure limits for 13
carcinogenic substances. New EU-wide exposure limits for the substances were
needed because EU countries have varying national limits, meaning companies in
countries with less-stringent controls could “benefit from an undue competitive
advantage”, [1,3-butadiene, acrylamide, bromoethylene, chromium (VI) compounds,
ethylene oxide, hardwood dusts, hydrazine, o-toluidine, respirable crystalline silica,
refractory ceramic fibers and vinyl chloride monomer].21
The European Union (EU) Labelling Guide distinguishes three categories of
human, animal and suspected carcinogens, respectively. This system had been
introduced in the early 1980s, based on pre-existing systems at national levels, such
as that of the German Senate Commission of the DFG for the investigation of health
hazards in the work area (“MAK Commission). 22,23
The Health and Safety Executive (HSE) in the United Kingdom has advanced
from 2002 (and amended in nthe following years) appropriate legislation The
Control of Substances Hazardous to Health (COSHH) that required employers to
control substances that are hazardous to health, including exposure to carcinogens
( http://www.hse.gov.uk/coshh/index.htm ). The UK currently follows the Chemicals
Hazard Information and Packaging for Supply Regulations 2009 (CHIP) for chemical
hazard classification which uses Risk phrases and Safety Phrases to identify chemical
hazards. CHIP also assigns indications of danger to substances, some of which have
sub categories such as carcinogenic category 1, 2 and 3. CHIP carcinogen categories
are often written in Material Safety Data Sheets (MSDS) as "Carc. Cat." (http://
www.hse.gov.uk/chemical-classification/index.htm ).
The EU directives on the protection of health and safety at work have had a
big impact, laying down basic principles for all sectors of activity, especially general
responsibilities of employers. These directives are legally binding and have to be
transposed into national laws by the member states. However, continuous
surveillance of compliance with protection guidelines is still needed across all EU
countries.24,25
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In Japan the Industrial Safety and Health Law (administerd by the Ministry of
Health, Labour and Welfar) was initiated in 1972 to regulate chemical carcinogens
which were used in the workplaces and to prevent exposure and occupational
cancers.26
Figure 3. A carcinogen is a substance that causes a normal cell to change into a
cancerous cell (uncontrolled cell growth) that can multiply to form a mass of
neoplastic tissue (tumour) [http://www.scienceclarified.com/Ca-Ch/Carcinogen.
html#ixzz4ful7Dz9H ].
Canada uses some basic information on carcinogens from IARC and American
Conference of Governmental Industrial Hygiensits of the US. In 2015, the
Government of Canada published the Hazardous Products Regulations (HPR), which,
in addition to the amendments made to the Hazardous Products Act (HPA), modified
the Workplace Hazardous Materials Information System (WHMIS) 1988, [Hazard
Specific Issues Substances assessed for carcinogenicity, 1988], to incorporate the
Globally Harmonized System of Classification and Labelling of Chemicals (GHS) for
workplace chemicals.27
Australia is another industrialised country which supports the strict
regulation of hazardous and carcinogenic chemicals in the working environment and
for the protection of the environment. In 2012, following the adoption of the model
Work Health and Safety Regulations, Australia began to transition to the Globally
Harmonized System of Classification and Labelling of Chemicals (GHS), an
international system used to classify and communicate chemical hazards. The GHS
was created by the United Nations as a single worldwide methodology for chemical
classification, labelling and Safety Data Sheets (SDS). The system ensures that users
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are provided with practical, reliable and easy to understand information on chemical
hazards, and can take the appropriate preventive and protective measures for their
health and safety. The GHS is expected to provide significant trade benefits to
industry as well as improved health and safety outcomes. In 2017 the GHS wiill take
full effect in Australia. Australia introduced the code of practicer for carcinogens in
1995 [NOHSC, National Code of Practice for the Control of Scheduled Carcinogenic
Substances, NOHSC: 2014(1995)] which is a model regulation for the control of
workplace hazardous substances (1994) and the Dangerous Goods Standard
(2001).28
Assessment Tests to Prove the Protential of Substances for
Carcinogenicity
Chemical substances, physical and biological agents can be tested to prove
that can cause cancer to humans. This apsect can be tested only through
epidemiological studies and statistical analysis of data. Scientists get much of their
data about whether substances or mixtures might cause cancer by using 4 different
methods: See references in the following text.
1. Cell-based Assays (in vitro). Experimental laboratory tests with cell cultures.
Several assay systems with rapid and reliable methods for this purpose have
been introduced in microorganisms, plant and mammalian cells.
2. Experimental animals (in vivo) (mice, rats) (in vivo tests) which are produced in
special laboratories and under specific stardard procedures and technical
protocols.
3. Carcinogens to humans are identified by epidemiological studies with a large
number of subjects in a long-term occupational or environmental exposure
studies that evaluate risk through statistical morbidity and mortality cancer
data among the subjects. Cancer pidemiology is concerned with events that
occur in populations (groups of people, not separate individuals),
differentiating epidemiology from clinical medicine. Epidemiological studies
are concerned not only with people who get a disease, but also with those who
do not, and in particular how these two groups may differ. Epidemiology is the
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only source of direct scientific evidence about exposure effects and the
preventability of disease within human populations.
4. Methodology of Quantitative Structure-Activity Relationships (QSARs) is
another method of data models to predict the potential carcinogenic chemicals
(rapid and inexpensive method, but with limitations). QSAR models first
summarize a supposed relationship between chemical structures and biological
activity (potential for carcinogenicity) in a data-set of chemicals and then QSAR
models can predict the activities of new chemicals.
Cell-based Assays (in vitro) for Carcinogenicity Assessment
Cell-based assays (CTAs) have long been proposed as in vitro methods for the
identification of potential chemical carcinogens. Mutagenicity and genotoxicity
assays can be used to indicate possible carcinogenic substances. The in vitro cell
transformation and gap junction intercellular communication can be used to identify
possible carcinogens, including non-genotoxic carcinogens. The in vitro
carcinogenicity assays methods are significantly faster and less expensive than in
vivo. Cell transformation assays are based on detecting phenotypic changes induced
by chemicals in mammalian cell cultures. The most widely used of these assays are
the Syrian hamster embryo (SHE) assay. Despite showing good correlation with
rodent bioassay data, concerns over the subjective nature of using morphological
criteria for identifying transformed cells and a lack of understanding of the
mechanistic basis of the assays has limited their acceptance for regulatory purposes.
However, recent drivers to find alternative carcinogenicity assessment
methodologies, such as the Seventh Amendment to the EU Cosmetics Directive, have
fuelled renewed interest in CTAs. Research is currently ongoing to improve the
objectivity of the assays, reveal the underlying molecular changes leading to
carcinogenic transformation and explore the use of novel cell types.29-31s
The increasing number of assays and the numerous results on carcinogenicity
and mutagenicity of hazardous chemicals initiated databases.The European EURL
ECVAM Genotoxicity and Carcinogeniucty Consolidated Database compiled available
genotoxicity and carcinogenicity data for Ames test positive chemicals originating
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from different sources. This database contains results on the following tests: in vitro
tests (Ames, mouse lymphoma Tk+/- [MLA] or gene Hprt locus, micronucleus [MN],
chromosome aberration [CA]); in vivo tests (MN, CA, UDS, transgenic models, DNA
breakage [Comet and alkaline elution assay]) and rodent data on carcinogenicity. 32
The Ames Assay for Carcinogenicity. This is a famous in vitro test that was
developed in the 1970‟s by Bruce Ames (Prof. of Biochemistry at University of
California at Berkeley), as a fast and sensitive assay of the ability of a chemical
compound or mixture to induce mutations in DNA. Because the assay does not use a
live animal model, it is inexpensive, easy, and fast. Bruce Ames published his work in
a series of papers, including “Identifying Environmental Chemicals Causing Mutations
and Cancer” in the journal Science (vol. 204, 1979).
Bruce Ames developed a test using histidine auxotrophic
mutants, several strains of the bacterium Salmonella
typhimurium that carry mutations in genes involved in
histidine synthesis
Animal tests for carcinogenicity use mainly
mice and rats. Experiments last 2,5 years
Figure 4. The potential of carcinogenicity for chemicals can de performed by in vitro
tests (cell cultures) and by in vivo tests in experimental animals (mice, rats).
The Ames test was critical in linking mutations in DNA to carcinogenesis. The
test identified many mutagens including pesticides such as DDT, the flame retardant
„tris-BP‟, and mutagenic compounds in commercial hair dyes. Although about 75%
of chemicals that are positive in the Ames test are found to be rodent carcinogens,
not all substances that cause cancer in laboratory animals are mutagenic in this
assay. However, the ease, rapidity (results in 3-4 weeks) and low cost of the test
make it an important tool for screening substances for potential carcinogenicity.
Several modifications of the Ames test protocol have been used over the years in
special circumstances.33 The Ames test is used for the indenyification of carcinogenic
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substances for the REACH programme of hazardous chemicals in the European
Union.34
Carcinogenicity Animal Studies (in vivo).
Most studies of potential carcinogens expose the laboratory animals to
doses that are much higher than common human exposures. This is so that cancer
risk can be detected in relatively small groups of animals (in groups of 50 for both
sexes and for every dose). It is not always clear if the results from animal studies will
be the same for people as they are normally exposed to a substance. The
carcinogenic effects seen in laboratory studies with very high doses of a substance
may not be the same at much lower doses (environmentally realistic), or the effects
of a substance when it is inhaled may not be the same as if it is applied to the skin.
Also, the bodies of laboratory animals and humans don't always process substances
(metabolism) in the same way.
The conventional test for carcinogenicity is the long-term rodent
carcinogenicity bioassay described by the Organisation for Economic Cooperation
and Development (OECD) as Test Guideline (TG) 451. The objective of this test is “to
observe test animals for a major portion of their life span for the development of
neoplastic lesions” in various organs. The use of the results of laboratory animal
tests to predict human cancer is effective in identifying potential human carcinogens
before human exposure, permitting measures to be taken to prevent that exposure.
Figure 5. Dose/response in carcinogenicity test. The procedusre used to extrapolate
from high to low doses are different for assessing carcinogenic effects and non-
carcinogenic effects. In the first case it is considered that there is no threshold and
mathematical models are generally used to providse estimates of carcinogenic risk at
low dose levels. [US National Library of Medicine, Dose-response assessment,
https://toxtutor.nlm.nih.gov/06-003.html ].
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The purported, and highly publicized, faults of these tests, when examined
critically, are shown not to be significant. Most chemicals are not carcinogenic; only
about 1 in 10 is proved to be truly carcinogenic. The high doses used to maximize
sensitivity (where animals after 2 years develop carcinogenic tumours) do not
produce false positives. All human carcinogens are carcinogenic in laboratory
animals, and almost all animal carcinogens for which there is human exposure, when
analyzed by epidemiological studies, show responses that are not statistically
different. Most carcinogens are not banned, as long as they are useful materials in
industry, some are regulated to reduce risk.35-37
Alternative Approaches to Animal Testing for Carcinogenicity
For many decades there was a continuous effort in industrialised countries
such as USA, Japan and in the European Union, to find alternative testing
approaches which avoid the use of experimental animals wherever possible. In
toxicological tests that replacement was not possible for practical reasons, the
development of methods which use fewer animals or cause least harm to the
animals were supported. This ‘Three Rs Principle’ (replacement, reduction and
refinement of animal use) was present in all relevant EU legislations. In early 2003,
the 7th amendment to the European Union’s Cosmetics Directive (76/768/EEC) was
adopted. It stipulated an immediate end to animal testing in the EU for cosmetic
products and a complete ban of animal testing for ingredients by 11 March 2009,
irrespective of the availability of alternative methods. The animal testing ban was
reinforced by a marketing ban on all cosmetic ingredients or products tested for the
purposes of the Directive outside the EU after the same date. The only exception
related to animal testing for the more complex toxicological endpoints such as
repeated dose toxicity, reproductive toxicity and toxicokinetics, for which the
deadline was set to 11 March 2013, respecting that alternatives for these human
health (-related) effects would not be available by 2009. The Directive foresees that
the 2013 deadline could be further extended in case alternative and validated
methods would not be available in time. Further to the adoption of the 7th
Amendment, the European Commission was tasked with reporting regularly on
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progress and compliance with the deadlines as well as possible technical difficulties
in complying with this ban.38,39
The need for alternatives to the traditional use of animals in toxicity testing
was officially recognized by the U.S. government in 1993 with passage of the NIH
Reauthorization Act. Requirements under the Act led to the establishment of an ad
hoc committee called the Interagency Coordinating Committee for the Validation of
Alternative Methods (ICCVAM) with representatives from 15 U.S. federal regulatory
and research agencies. In 2007, the U.S. National Research Council (NRC) released a
report titled “Toxicity Testing in the 21st Century: A Vision and a Strategy,” which
addressed the limitations of animal-based toxicology tests and called for a shift
toward non-animal testing methods. The report was issued in response to a request
from the U.S. Environmental Protection Agency (EPA), asking for the NRC to conduct
a comprehensive review of toxicity testing methods. In their report, the NRC
summarized that “advances in toxicogenomics, bioinformatics, systems biology,
epigenetics, and computational toxicology could transform a system based on
whole-animal testing to one founded primarily on in vitro methods that evaluate
changes in biologic processes using cells, cell lines, or cellular components,
preferable of human origin.”40
In 2008, the EPA and the U.S. National Institutes of Health’s (NIH) National
Toxicology Program and Chemical Genomics Center signed a “Memorandum of
Understanding” to follow the NRC report’s vision and begin developing new methods
of toxicity testing that involve the use of lab grown human cells instead of animals.
After the EPA began evaluating 300 chemicals using the new methods, they found
that it allows for thousands of chemicals to be tested at once. This method is much
faster, less expensive, and does a better job of protecting human health. According
to former NIH Director Zerhouni, “It won’t mean that animal testing will disappear
overnight, but it signals the beginning of the end.” Today, the EPA is in the process of
building virtual human organs. The EPA's "virtual tissue" researchers are developing
a set of computer simulations that may one day be able to identify the risks posed by
industrial pollutants and pesticides, saving thousands of animals from toxicity tests.41
The U.S. Environmental Protection Agency (EPA) has contributed to the
development and evaluation of high-throughput in vitro alternative toxicology
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methods for carcinogenicity through a special ToxCast™ programme [
http://epa.gov/ncct/toxcast/] which was initiated in 2007 with the goal of testing a
large set of environmentally relevant chemicals in a correspondingly broad range of
in vitro high-throughput screening (HTS) and high-content screening (HCS) assays.
Toxcat was aimed to provide a data set that could be used to evaluate the value of
different assay technologies and computational/modelling approaches.42
ToxCast has screened more than 1,800 chemicals in as many as 700 assays.
Several applications and modelling approaches have been developed and published,
mainly focusing on the first 300 ToxCast chemicals, which are primarily data-rich
pesticide active ingredients. At present the application of these approaches is
formulated for the larger Phase II data set, which includes a more diverse set of
chemicals. All of these data are publically available (researchers from other countries
can perform independent evaluations and analyses through the ToxCast website and
the ToxCast dashboard (http://actor.epa.gov/dashboard). ToxCast is one part of the
U.S. multiagency toxicity testing programme called Tox21, which comprises
researchers from the National Institutes of Health (NIH), the National Toxicology
Programme (NTP), the Food and Drug Administration (FDA), and the U.S. EPA. The
programme Tox21 has many of the same aims as ToxCast, but covers a broader
chemical space for a subset of HTS assay technologies.43
Quantitative Structure-Activity Relationships (QSARs) for Determining
Carcinogenic Potency
Determining the carcinogenicity and carcinogenic potency of new chemicals
is both an-intensive and time-consuming process. In order to expedite the screening
process, a toxicologist can identify alternative toxicity measures of shorter duration
for carcinogenic potency or develop Quantitative Structure-Activity Relationship
(QSAR) models to predict the cancer slope factors of environmental chemicals.
QSAR studies have become particularly popular in the rational design of
drugs and pesticides. Much has been published on the principles of QSAR and the
applications to assess toxic chemicals. The scientific literature contains numerous
QSAR studies on chemical mutagens and carcinogens and many recent advances
have been achieved in this rapidly emerging field through the contributions of
15
leading experts from around the world. Also QSAR models canb be used in predicting
and designing compounds for synthesis and testing of cancer drugs. There are many
examples that QSAR models can contribute to the elucidation of mechanisms, to
identifying toxic chemicals solely by their chemical structure, and to the design of
safer chemicals. There is extensive bibliography on reviews of QSAR models.44
There are many QSARs models for the prediction of mutagenicity and
carcinogenicity, carried out in a collaboration between the European Chemicals
Bureau Group on Computational Toxicology and the Italian Istituto Superiore di
Sanita’. The studied models can be interpreted mechanistically, agree with, and/or
support the available scientific knowledge, and exhibit good statistics. The
genotoxic-based QSAR models had an accuracy of about 65% for rodent carcinogens,
and about 75% for Salmonella mutagens. Overall, the QSAR-based predictions are
able to significantly enrich the target of safer chemicals, contribute to the
organization and rationalization of data, elucidate mechanisms of action, and
complement data from other sources.45
Epidemiological Studies for Risk Assessment of Carcinogens
The Greek doctor Hippocrates described for the first time the appearance of
carcinogenic tumours in humans as 'karkinos'. Galeno introduced the word neoplasia
as an abnormal growth of a body area. The English surgeon Percivall Pot was first to
recognize in 1775 the casual relationship between exposure to environmental
substances (chimney soot) and tumour of the skin of the scrotum of London chimney
sweeps. Epidemiologic investigations enabled scientists to conclude that neoplasic
pathogenesis involves accummulation of cellular DNA damage, and is a complex
process which can be divided into three distinct stages: initiation, promotion and
progression. Epidemiologic studies provide a great deal of information about
exposure to carcinogenic substances, are retrospective with a large number of
individuals so that the studied to have increased sensitivity. Observational studies
are particularly susceptible to the effects of chance, bias and confounding and must
be taken into account in the design and analysis stages of an epidemiological
study.When the number of individuals is small the confounding factors can affect the
results. A potential confounder is any factor that might have an effect on the risk
16
assessment. Confounding factors (age, socioeconomic, gender, occupation,
conditions of exposure, etc) are factors that can have direct causal link to the
disease, as well as factors that are proxy measures for other unknown causes.
Matching the number of individuals with controls is very important. Epidemiological
studies usually allow for latent periods of 15 years or more for cancer to develop.46,47
Epidemiological techniques have been useful for identifying exposure to high
carcinogenic concentrations. Depsite the progress in elucidation of cancer initiation
and progression, it is difficult to understand the individual contribution of a certain
chemical within a complex situation like environmental contamination. Chemical
carciogenesis involves multi-stage mechanisms, epigenetic events, oncogene
overexpression, activation of protooncogenes, inactivation of tumor-suppressor
genes, chromosomal translocations, deletions, gene amplification, and numerical
chromosome changes. The final development of neoplastic tumours is the result of
many biological trasformations with prolonged latent period.48,49
For decades epidemiologists collected data on the risk to develop cancer by
prolonged and high levels of exposure in occupational environments. Biomarkers of
cancer types were used to indentify biological changes and morbidity and mortality
were recorded by medical examinations and death certificates. Cancers were
estimated with chronic studies and compared with various environmental exposure
rates. The individual contribution to this risk derived from specific carcinogenic
chemicals was elucidated by molecular epidemiological techniques. Measurements
of special biomarkers of exposure, of effect and of susceptibility provide information
of potential benefit for epidemiological and cancer risk assessment.50
What Are the Most Important Causes of Cancer?
Most of the cancer experts and medical statiticians agree that cancer in the
last decades is the second most important cause of death (after the cardiovascular
diseases) in the developed industrial countries and accounts for nearly 25% of
deaths. The World Health Organisation (WHO) estimates that, worldwide, there
were 14 million new cancer cases diagnosed and 8.2 million cancer-related deaths in
2012 (GLOBOCAN 2012, produced by the IARC, their most recent data). Cancer is
17
considered a disease of old age and is the result of the accumulation of cellular DNA
mutations. There are said to be over 250 different types of human cancer and are divided
into five broad groups (carcinomas, sarcomas, lymphomas, leaukemias, adenomas).
Figure 6. There is a series of publications on carcinogens, guidelines for safe handling
and risk assessment. Castegnano M, Sansone FB. Chemical Carcinogens. Springer-
Verlag, Berlin, 2012. Searle CE. Chemical Carcinogens. ACS Monograph No. 173,
American Chemical Society, Washiungton DC, 1976. Sittig’s Handbook of Toxic and
Hazardous Chemicals and Carcinogens, 6th edition. William Andrew, London, 2011
Cancer occurs when a cell's gene mutations make the cell unable to correct
DNA damage and unable to commit suicide. Similarly, cancer is a result of mutations
that inhibit oncogene and tumor suppressor gene function, leading to uncontrollable
cell growth and finally into a neoplastic tumour. The initiation and progression of
carcinogenic mechanisms take many yearts and their latent period depends of a great variety
of molecular factors relating to cell metabolism (in addition to mutagenic mechanisms,
chemicals may heritably alter cells by epigenetic mechanisms and enhance the clonal
expansion of altered cells). 51
Cancer and Lifestyle Factors.
The perception of cancer as a deadly and incurrable disease among people was
widespread for decades and still continues to cause deep-seated fears in lay people
and make it difficult to experts to challenge some of the popular myths. Mortality
and morbidity data showed that extrinsic or “environmental” factors were the main
causes of the neoplastic diseases in humans. Diet and smoking are considered the
most important cancer causing factors (responsible for more than 50% of deaths
18
from cancers). When medical experts refer to diet, they mean excessive eating
(obesity), salty and fried red meat, excess consumption of processed red meat
(bacon, chaussages, etc), animal fat, less than 5 portions of fruit and vegetables, lack
of exercise and drnking regularly excessive alcoholic drinks. All these factors can
increase cancer risk in the long term. Smoking (active and passive) is considered now
as the most dangerous extrinsic factor for lung cancer and other types of cancer.
Also, cancer is caused by chronic infections from helicobacter pylori, hepatitis B virus
(HBV), hepatitis C virus (HCV) and some types of human papilloma virus (HPV).
Excessive exposure to the sun (sunburns) at young age and having unsafe sex can
contribute to the development of cancer at later stages in life. Older age is
associated with an increase in the incidence of cancer like other degenerative
diseases.52-57
The patterns of new cases of cancer (diagnosed) and mortality changed in the
last decades as the lifestyle and exposures of humans change. The World Cancer
Research Fund International in London has started The Continuous Update Project.
This is an ongoing programme to analyse global research on how diet, nutrition,
physical activity and weight affect cancer risk and survival. Among experts worldwide
it is a trusted, authoritative scientific resource, which underpins current guidelines
and policy for cancer prevention.58
Breast cancer is the most frequently diagnosed cancer and the leading cause of
cancer death among females worldwide, with an estimated 1.7 million cases and
521,900 deaths in 2012, accounting for 25% of all cancer cases and 15% of all cancer
deaths among females.59 Lung cancer. An estimated 1.8 million new lung cancer
cases occurred in 2012, accounting for about 13% of total cancer diagnoses and the
leading cause of cancer death among males in 2012. Most lung cancers could be
avoided by eliminating smoking. Colorectal cancer is the third most commonly diagnosed
cancer in males and the second in females, with an estimated 1.4 million cases and
693,900 deaths occurring in 2012. Stomach cancer. An estimated 951,000 new cases
and 723,000 deaths occurred in 2012. Incidence rates are highest in Eastern Asia
(Korea, Mongolia, Japan, and China), Central and Eastern Europe, and South America
and lowest in US, Canada, West Europe and most parts of Africa. Regional variations
in part reflect differences in dietary patterns (red meat and animal fat, consumption
19
of fruit and vegetables), food storage (refrigiration affect positively ther quality of
food), and the availability of fresh produce, as well as the prevalence of Helicobacter
pylori infection. A steady decline in stomach cancer incidence and mortality rates has
been observed in the majority of more developed countries in Northern America and
Europe since the middle of the 20th century (changes in diet patterns, fresher food,
less meat, olive oil, Mediterranean diet, antioxidants, vitamins).60-63
Exposure to Carcinogens in the Working Environment.
Scientists established for many centuries that certain jobs have higher risks of
cancer, because of exposures to some materials, chemical carcinogens, ionizing
radiation, and some occupational practices. Occupational epidemiological studies in
industrialised countries established that occupational exposures are responsible for
nearly 4-5% of cancer cases. Benzene, asbestos, chromium(VI), benzidine (1,1'-
biphenyl-4,4'-diamine), vinyl chloride, polycyclic aromatic hydrocarbons, etc, are well
known occupational carcinogens. Safe work rules and strict legislation in
industrialised countries in the last decades have reduced substantially the dangers of
occupational exposures. Most dangerous carcinogenic chemicals have been banned
for many years and employers are responsible for protective measures and safety
regulations in the working environment. 64-66
Exposure to certain agricultural chemicals (pesticides) could increase cancer risk.
Exposure to diesel engine exhaust (garages, petrochemical industry, etc) can
increase cancers of the resporatory system. Exposure to asbestos fibers, silica dust
and other minerals (mines) and metal extraction occupations have been poroved to
be responsible for most of respiratory cancers. Exposure to coal products, organic
paints, solvents, wood dusts can increase cancer risk. Smoking can act synergistically
with other occupational carcinogens increasing the risk for cancers at a very early
age of the working life. Certain chemicals at various occupations (chlorinated
chemicals, nickel, cadmium, vinyl chloride, polycyclic aromatic hydrocarbons,
dioxins, etc) can increase the risk of developing cancer. Legally, these chemicals must
carry hazard warnings and their use must be strictly controlled or the workers must
wear protective equipment to reduce exposure. Where these chemicals are still in
use, they are heavily regulated to keep workers’ exposure within safety limits.67-69
20
Environmental Carcinogens, air and water pollution
Water pollution is a severe environmental worldwide problem that urgently
requires monitoring, measures to reduce pollution and recycling of industrial and
municipal water waste. Every day, millions of tonnes of municipal sewage, industrial
and agricultural waste are discharged into the world׳s water equivalent of the weight
of the entire human population. The UN estimates that the amount of wastewater
produced annually is about 1500 km3, six times more water than exists in all the
rivers of the world. It is estimated that 70% of freshwater worldwide is used for
agricultural irrigation. 70-72.
Nowadays, more than 700 emerging pollutants, their metabolites and
transformation products, are listed as present in the European aquatic environment
(www.norman-network.net). Emerging pollutants (EPs) are defined as synthetic or
naturally occurring chemicals that are not commonly monitored in the environment
but which have the potential to enter the environment and cause known or
suspected adverse ecological and (or) human health effects. The prominent classes
of these chemicals are: industrial chemicals, pharmaceuticals in municipal waste and
waste from stock farming (antibiotics, hormones, veterinary medicines), pesticide
residues, fertilisers (agriculture), disinfection by-products (municipal and, industrial
waste), wood preservation.73
Urban Air Pollution and Cancer Risk
From the 1960s scientists focused on gaseous air pollutants (sulphur dioxide,
SO2, nitrogen oxides, NOx, ozone, O3, carbon monoxide, CO and smoke). But from
the 1980's air pollution studies turned their attention to adverse health effects of
inhalable ambient particulates, especially the link between respiratory diseases, lung
cancer and ambient particulate matter (PM). Suspended PM10 and PM2.5
(aerodynamic diameter in μm) penetrate into the lungs’ alveoli carrying highly toxic
substances (carcinogenic heavy metals, PAHs, nitropyrenes, etc) and can be trapped
in the pulmonary parenchyma. Epidemiological time-series and prospective cohort
studies gave supportive evidence for a positive association of increased morbidity
and mortality of the respiratory system. Health effects included decreased lung
function, increased hospitalizations, increased cardiovascular and lung cancer
mortality.74-79
21
The association between ambient air pollution exposure and lung cancer risk
has been investigated in prospective studies and results showed that long-term
exposure to air pollution is a strong cause of lung cancer. A systematic review of 524
papers analysed the relationships between ambient air pollution and biological
markers of dose and early response. The evidence of biomarkers covered the whole
spectrum of disease onset and progression.80 In the last years numerous
epidemiological studies estimated the associated risk for lung cancer after acute and
chronic exposure to particulate matter, traffic air pollution, distance from heavy
traffic roads, etc.81-84
Sunlight Exposure and Skin Cancer
Exposure to sun and sunbeds can be damaging and lead to skin cancer. There
are two manui types of ultraviolet rays that can damage the skin., UV-A (long wave,
400-315 nm) penetrates deep into the skin causing ageing but contributes much less
towrds sunburns than UV-B rays (280-315 nm), which are many times higher energy
and are responsible for the majority of sunburns. UV-B causes tanning, wrinkling,
aging of the skin and skin cancer. The UV-C section (<280 nm, short wave) of rays is
more dangerous, but it is copmpletely blocket our by the ozone layer in the
stratosphere. UV-A rays account for 90-95% of UV radiation that reaches the Earth.
While UV-B is only 5-10% of solar radiation, but its high energy damages surface
epidermal layers and causes sunburns. Initially UV-A was considered not harmful or
less harmful than UV-B, but today it is known to contribute to skin cancer via indirect
DNA damage (free radicals such as reactive oxygen species, ROS, such as hydroxyl
radicals, HO● and oxygen radicals, RO● , which in turn can damage DNA (single-
strand breaks in DNA), while the damage caused by UVB includes direct formation of
thymine dimers or other pyrimidine dimers, and double-strand DNA breakage.85,86
Exposure to sunlight for several years damages skin and there is an increased
chance of developing one of the forms of skin cancer. High levels of chronic exposure
(working outdoors), is more often associated with squamous cell tumours. Malignant
melanoma (MM), although rarer, is the most serious of the skin cancers. The
incidence of Non-melanoma skin cancer (NMSC) increased rapidly in the last decades
in white populations in Europe, the U.S., Canada, and Australia (average increase
was 3–8% per year since the 1960s). The rising incidence rates is due to a
22
combination of increased sun exposure or exposure to UV, outdoor activities,
changes in clothing style, increased longevity, and ozone depletion. Malignant
melanoma (MM) incidence is much lower compared to NMSCs but has been rising in
fair-skinned populations throughout the world for several decades. 87-89
Figure 7. Melanoma is the 3rd most common skin cancer and the most aggressive.
Some people have a higher risk of developing skin cancer (fair skin, freckles, a family
history of skin cancer, etc). Non-melanoma skin cancers are the most common and
two main types are squamous cell carcinomas (SCC) and basal cell carcinomas (BCC).
Several studies have shown that UV induces unique types of p53 mutations in
skin cancers at a high frequency. Analogous to human skin cancers, skin cancers
induced in laboratory mice by UV radiation also display UV signature p53 mutations
at a high frequency.90,91
National and International Databases on Carcinogens and Hazardous
Chemicals
1. Carcinogenic Potency Database (CPDB)
The Carcinogenic Potency Databas (CPDB) provides historical information from the
years 1980 - 2011. It is no longer updated. CPDB reports analyses of animal cancer
tests on 1547 chemicals. Results for each chemical are searchable on the Web site of
the National Library of Medicine (NLM®)Toxicology Data Network (TOXNET®). CPDB
includes 6,540 chronic, long-term animal cancer tests, both positive and negative for
carcinogenicity, from the general published literature as well as the National Cancer
Institute and the National Toxicology Program (NTP). Tests are used in support of
cancer risk assessments for humans. CPDB was developed by the Carcinogenic
Potency Project (University of California, Berkeley) and Lawrence Berkeley
NationalLaboratory.Web[https://www.nlm.nih.gov/pubs/factsheets/cpdbfs.html].
23
2. Mopnographs of IARC on the Evaluation of Carcinogenic Risks to Humans
(International Agency for Research on Cancer, Lyon), Agents classified by the IARC
Monographs, Vols 1-118 [http://monographs.iarc.fr/ENG/Classification/].
The number of carcinogens under the classification system are: Group 1: 120 agents,
Group 2A : 81, Group 2B: 294, Group 3: 500, Group 4 : 1.
IARC Group 1 (120). Carcinogenic to humans
Substances: 2-Naphthylamine, Acetaldehyde associated with consumption of
alcoholic beverages, 4-Aminobiphenyl, Aflatoxins, Aristolochic acids, and plants
containing them, Arsenic and inorganic arsenic compounds, Asbestos,
Azathioprine, Benzene, Benzidine, and dyes metabolized to Benzo[a]pyrene,
Beryllium and beryllium compounds, Chlornapazine (N,N-Bis(2-chloroethyl)-2-
naphthylamine), Bis(chloromethyl)ether, Chloromethyl methyl ether, 1,3-
Butadiene, 1,4-Butanediol dimethanesulfonate (Busulphan, Myleran),
Cadmium and cadmium compounds, , Chlorambucil, Methyl-CCNU (1-(2-
Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea; Semustine) Chromium(VI)
compounds, Ciclosporin, Clonorchis sinensis (infection with), Cyclophosphamide,
1,2-Dichloropropane, Diethylstilboestrol, Epstein-Barr virus, Estrogen therapy,
postmenopausal, Ethanol in alcoholic beverages, Erionite, Ethylene oxide,
Etoposide alone, and in combination with cisplatin and bleomycin, Fluoro-edenite
fibrous amphibole, Formaldehyde, Gallium arsenide, Helicobacter pylori (infection
with), Hepatitis B virus (chronic infection with), Hepatitis C virus (chronic infection
with), Human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus), Human
immunodeficiency virus type 1 (infection with), Human papillomavirus type 16, 18,
31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66, Human T-cell lymphotropic virus type 1
(HTLV-I), Lindane, Melphalan, Methoxsalen (8-Methoxypsoralen) plus ultraviolet A
radiation, 4,4'-Methylenebis(2-chloroaniline) (MOCA), MOPP and other combined
chemotherapy including alkylating agents, Mustard gas (Sulfur mustard), 2-
Naphthylamine, Neutron radiation, Nickel compounds, 4-(N-Nitrosomethylamino)-1-
(3-pyridyl)-1-butanone (NNK), N-Nitrosonornicotine (NNN), Opisthorchis
viverrini (infection with), Outdoor air pollution, Particulate matter in outdoor air
pollution, 2,3,4,7,8-Pentachlorodibenzofuran, 3,4,5,3’,4’-Pentachlorobiphenyl(PCB-
126), Phosphorus-32, as phosphate, Plutonium, Radioiodines, short-lived isotopes,
including iodine-131, from atomic reactor accidents and nuclear weapons
detonation (exposure during childhood), Radionuclides, α-particle-emitting,
internally deposited, Radionuclides, β-particle-emitting, internally deposited,
Radium-224 and its decay products, Radium-226 and its decay products, Radium-
228 and its decay products, Radon-222 and its decay products, Schistosoma
haematobium (infection with), Silica dust, crystalline (inhaled in the form of quartz
or cristobalite from occupational sources), Talc containing asbestiform fibres,
Tamoxifen, ..2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), Thiotepa (1,1',1"-
Phosphinothioylidynetris, Thorium-232 and its decay products, administered
intravenously as a colloidal dispersion of thorium-232 dioxide, Treosulfan,
Trichloroethylene, o-Toluidine, Vinyl chloride
24
Radiations: Ionizing radiation (all types), Ultraviolet radiation ncluding solar
radiation, X-Radiation and gamma radiation
Mixtures:, Aflatoxins (naturally occurring mixtures of), Alcoholic beverages, Areca
nut, Betel quid with tobacco, Betel quid without tobacco, Coal-tar pitches, Coal-
tars, Coal indoor emissions from household combustion of Engine exhaust, diesel,
Estrogen-progestogen menopausal therapy, (combined), Estrogen-progestogen oral
contraceptives (combined)3, Fission products, including Strontium-90, Leather dust,
Mineral oils, untreated and mildly treated, Paints containing benzene, Phenacetin,
analgesic mixtures containing, Plants containing aristolochic acid, Polychlorinated
biphenyls, dioxin-like, Processed meats, consumption of, Salted fish (Chinese-style),
Shale-oils, Soot (as found in occupational exposure of chimney sweeps), Wood dust
Exposure circumstances: Acheson process, occupational exposure associated with,
Acid mists, strong inorganic, Aluminium production, Auramine production, Boot
and shoe manufacture and repair (see leather Dust and benzene), Chimney
sweeping (see Soot), Coal gasification, Coal tar distillation, Coke (fuel) production,
Furniture and cabinet making (see wood dust), Haematite mining (underground)
with exposure to radon, Iron and steel founding (occupational exposure to),
Isopropanol manufacture (strong-acid process), Glass, making of Magenta dyes,
manufacture of Painting (see benzene), Paving and roofing with coal tar pitch,
Rubber manufacturing industry, Sandblasting (see silica dust), Smokeless tobacco,
Tobacco smoke, second hand, Tobacco smoking, Ultraviolet-emitting tanning
devices.
Related terms
3. National Toxicology Program (USA)
The National Toxicology Program (NTP) is an interagency program in the USA
whose mission is to evaluate agents (and carcinogens) of public health concern by
developing and applying tools of modern toxicology and molecular biology. NTP was
established in 1978 by Joseph A. Califano, Jr., Secretary of Health, Education and
Welfare (today known as the Department of Health and Human Services, USA). The
program was created as a cooperative effort to: Coordinate toxicology testing
programs within the federal government of U.S., strengthen the science base in
toxicology, develop and validate improved testing methods and provide information
about potentially toxic chemicals to health, regulatory, and research agencies,
scientific and medical communities, and the public.92
More than 80,000 chemicals are registered for use in the USA. Every year and
an estimated 2,000 new ones are introduced in the market. The NTP program has
tested numerous chemicals and its results consitute the most important scientific
data on toxicology. But, ee do not know the effects of many of these chemicals on
our health. Relatively few chemicals are thought to pose a significant risk to human
health and a small percentage are potentially carcinogenic. The 14th National Report
of NTP was published in 2016.
4. California Environmental Protection Agency (CA EPA) : Chemicals Known
to the State to Cause Cancer or Reproductive Toxicity , - California
Proposition 65, - Safe Drinking Water and Toxic Enforcement Act Of 1986
25
California Department of Toxic Substance Control (CA DTSC) : Safer Consumer
Product Candidate Chemicals.
5. US Department of Health & Human Services - National Institutes of
Health (US NIH). Report on Carcinogens
6. European Union / European Commission (EU EC)
The EU classification of carcinogens is contained in the Dangerous Substances
Directive and the Dangerous Preparations Directive. It consists of three categories:
Category 1: Substances known to be carcinogenic to humans, Category 2: Substances
which should be regarded as if they are carcinogenic to humans, Category 3:
Substances which cause concern for humans.
Classification, Labelling and Packaging Regulation (CLP) - Classification and
Labelling Inventory - CMRs
European Chemical Substances Information System (ESIS) - PBT List
Regulation on the Classification, Labelling and Packaging of Substances
and Mixtures (CLP) Annex 6 Table 3-1 - GHS Hazard code criteria
Public Activities Coordination Tool for Risk Management Option Analysis
EU Community Strategy for Endocrine Disrupters - Priority List
Restrictions On The Manufacture, Placing On The Market And Use Of
Certain Dangerous Substances, Preparations And Articles - Carcinogens,
Mutagens & Reproductive Toxicants
Restrictions On The Manufacture, Placing On The Market And Use Of
Certain Dangerous Substances, Preparations And Articles - Excluding
Carcinogens, Mutagens & Reproductive Toxicants
Commission Regulation (EC) No 987/2008 Annex I & 2 Exemptions from
the Obligation to Register in acccordance with REACH article 2(7)a
Substances of Very High Concern for REACH Annex XIV authorisation
(Article 59).
European chemical Substances Information System (ESIS) database: information on
chemicals from various elements/databases, including: EINECS (European Inventory
of Existing Commercial Chemical Substances); ELINCS (European List of Notified
Chemical Substances); BPD (Biocidal Products Directive) active substances; PBT
(Persistent, Bioaccumulative, and Toxic) or vPvB (very Persistent and very
Bioaccumulative); CLP/GHS (Classification, Labelling and Packaging of substances and
mixtures); HPVCs (High Production Volume Chemicals) and LPVCs (Low Production
Volume Chemicals); IUCLID Chemical Data Sheets, and others
7. German Federal Environment Agency (FEA) : Administrative Regulation
on the Classification of Substances hazardous to waters into Water Hazard
Classes (Verwaltungsvorschrift wassergefahrdende Stoffe - VwVwS)
MAK Commission of Germany (Deutsche Forschungsgemeinschaft). (MAK,
Maximale Arbeitsplatz Konzentration). List of Substances with MAK & BAT
Values & Categories (occupational exposure limits ).
26
8. American Conference of Governental Industrial Hugiensits (ACGIH)
ACGIH is a charitable scientific organization in the USA that advances
occupational and environmental health. ACGIH publishes annual editions of the TLVs
and BEIs book and work practice guides. For nearly 80 years, ACGIH has been
respected for its dedication to the industrial hygiene and occupational and
environmental health and safety communities in the USA and internationally. The
ACGIH promoted the Threshold Limit Values (TLVs) and Biological Exposure Indices
(BEIs) as guidelines to assist in the control of health hazards in occupational
environments.
9. United Nations Environment Programme (UNEP)
--- Rotterdam Convention Prior Informed Consent (PIC) Annex III Chemicals
----Stockholm Convention on Persistent Organic Pollutants (POPs) -Annex A, B &
C and under Review
10. Danish (Q)SAR Database: repository of estimates from over 70 (Q)SAR models
for 166,072 chemicals; (Q)SAR models encompass endpoints for
physicochemical properties, fate, eco-toxicity, absorption, metabolism, and
toxicity.
11. Integrated Risk Information System (IRIS): database of human health effects
that may result from exposure to various substances found in the
environment; hazard identification and dose-response assessments for over
500 chemicals (EPA, USA).
12. International Programme on Chemical Safety (IPCS INCHEM) (U.N. World
Health Organization): public, searchable, peer-reviewed chemical safety-
related publications and database records from international bodies, including:
Concise International Chemical Assessment Document (CICADS); International
Chemical Safety Cards (ICSCs); Pesticide Data Sheets (PDSs); Screening
Information Data Set (SIDS) for High Production Volume Chemicals; and more.
13. International Toxicity Estimates for Risk (ITER) Database: Free internet
database of human health risk values and cancer classifications for over 600
chemicals of environmental concern; now a part of TOXNET. TERA Toxicology
Excellence for Risk Assessment [ http://www.tera.org/iter/ ].
14. Chemical Carcinogenesis Research Information System (CCRIS). CCRIS
is a toxicology data file of the National Library of Medicine’s (NLM) Toxicology
Data Network (TOXNET®), USA. It is a scientifically evaluated and fully
referenced data bank, developed and maintained by the National Cancer
Institute (NCI), USA. It contains over 9,000 chemical records with
carcinogenicity, mutagenicity, tumor promotion, and tumor inhibition test
results. Data are derived from studies cited in primary journals, current NCI
reports, and other special sources.
27
15. ECOTOX. Created and maintained by the U.S. EPA, Office of Research and
Development, and the National Health and Environmental Effects Research
Laboratory’s (NHEERL’s). The ECOTOX (ECOTOXicology) database provides
single chemical toxicity information for aquatic and terrestrial life. ECOTOX is a
useful tool for examining impacts of chemicals on the environment. Peer-
reviewed literature is the primary source of information encoded in the
database.
16. European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC)
(Brussels, Belgium)– Special Reports. ECETOC Special Reports are compilations
of data targeted to specific regulatory issues/demands. European Centre for
Ecotoxicology and Toxicology of Chemicals (ECETOC) – Technical Documents
ECETOC Technical Documents are scientific briefing papers, addressing
emerging issues.
17. GENE-TOX. Created by the U.S. Environmental Protection Agency (EPA), GENE-
TOX contains genetic toxicology (mutagenicity) test data, resulting from expert
peer review of the open scientific literature, on over 3,000 chemicals.
18. Organisation for Economic Co-operation and Development (OECD, Paris)
Existing Chemicals Database. The OECD Existing Chemicals Database contains
all documents associated with the final published assessment (profiles,
assessment reports and dossiers) for chemicals that have been or are being
investigated in the OECD Cooperative Chemicals Assessment Programme.
19. WHO/FAO Pesticide Data Sheets (PDSs). Prepared by WHO in collaboration
with FAO, PDSs contain basic toxicological information on individual pesticides
and basic information for the safe use of pesticides.
20. TOXLINE : The TOXLINE database is the National Library of Medicine’s (NLM)
bibliographic database for toxicology, a varied science encompassing many
disciplines. TOXLINE records provide bibliographic information covering the
biochemical, pharmacological, physiological, and toxicological effects of drugs
and other chemicals. It contains over 3 million bibliographic citations, most
with abstracts and/or indexing terms and CAS Registry Numbers.
28
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