Environment International 128 (2019) 417–429

Contents lists available at ScienceDirect

Environment International
journal homepage: www.elsevier.com/locate/envint

Review article

Carcinogenicity assessment: Addressing the challenges of cancer and T

chemicals in the environment
⁎
Federica Madia , Andrew Worth, Maurice Whelan, Raffaella Corvi
European Commission, Joint Research Centre (JRC), Ispra, Italy

A R T I C LE I N FO A B S T R A C T

Handling Editor: Robert Letcher Cancer is a key public health concern, being the second leading cause of worldwide morbidity and mortality after
Keywords: cardiovascular diseases. At the global level, cancer prevalence, incidence and mortality rates are increasing.
Carcinogenicity testing These trends are not fully explained by a growing and ageing population: with marked regional and socio-
Environmental health economic disparities, lifestyle factors, the resources dedicated to preventive medicine, and the occupational and
Chemical exposure environmental control of hazardous chemicals all playing a role. While it is difficult to establish the contribution
Cancer risk of chemical exposure to the societal burden of cancer, a number of measures can be taken to better assess the
REACH carcinogenic properties of chemicals and manage their risks. This paper discusses how these measures can be
informed not only by the traditional data streams of regulatory toxicology, but also by using new toxicological
assessment methods, along with indicators of public health status based on biomonitoring. These diverse evi-
dence streams have the potential to form the basis of an integrated and more effective approach to cancer
prevention.

1. Introduction
Cancer has become a significant public health concern, emerging
worldwide as the second leading cause of morbidity and mortality
among non-communicable diseases after cardiovascular diseases.
Global estimates for 2018, which cover 36 different cancers in 185
countries, report 18.1 million new cancer cases and approximately 9.6
million cancer-related deaths (Fig. 1) (Bray et al., 2018). The number of
new cancer cases is projected to increase to 24.1 million annually by
2030 and to 29.5 million by 2040. In addition, > 32 million people are
living with a cancer diagnosis (5-year prevalence), thus contributing
heavily to the toll on health systems (Ferlay et al., 2018; Global Cancer
Observatory, 2018). Population growth and ageing can only partly
explain the rising figures in incidence and mortality. A number of fac-
tors account for the increasing global burden of the disease and regional
disparities in tumour types. These factors are primarily associated with
each country's level of socioeconomic development and therefore in-
clude life styles, hygiene levels, environmental pollution, spread of
communicable diseases (e.g. HIV, HPV, or hepatitis B), and the eco-
nomic resources dedicated to preventive medicine and occupational
exposure control measures (Bray et al., 2012; Ferlay et al., 2013; Jing
et al., 2014; WHO Cancer Report, 2014). Nearly half of all new cancers
estimated for 2018 are in Asia, where 60% of the population lives.
Europe accounts for 23.4% of total cancer cases although it is home to
only 9% of the global population (Bray et al., 2018). In fact, estimated
rates of new cases (adjusted per population size and age) are highest in
more industrialised regions (ECIS, 2018; Global Cancer Observatory,
2018; WHO Cancer Report, 2014). The greatest impact in terms of
mortality is in low- and middle-income countries or those experiencing
significant industrial growth, many of which are ill-equipped to cope
with the escalating burden and cost of the disease (Bray et al., 2018;
WHO Cancer Report, 2014).
In Europe, cancer is the most frequently occurring form of non-
communicable disease and the second most common cause of death,
after cardiovascular diseases. Estimates for 2018 indicate 4.2 million
new cancer cases and 1.94 million cancer deaths, as reported by the
European Cancer Information System (Fig. 1): a much higher rate on a
per capita basis than the global figure (ECIS, 2018; Bray et al., 2018;
Global Cancer Observatory, 2018). This is in spite of major improve-
ments in diagnosis and therapy, and a slight decrease in deaths linked
to certain cancers.
Furthermore, 10 million people are living with a cancer within
5 years of being diagnosed (Arnold et al., 2015; Global Cancer
Observatory, 2018). A number of interrelated causes contribute to the
high cancer incidence in Europe. In particular, these include: 1) life-
styles typical of industrialised countries (high very high HDI) (Colditz

⁎
Corresponding author at: European Commission, Joint Research Centre (JRC), Ispra, Italy, Via E. Fermi 2749, I-21027.
E-mail address: federica.madia@ec.europa.eu (F. Madia).

https://doi.org/10.1016/j.envint.2019.04.067
Received 4 January 2019; Received in revised form 10 March 2019; Accepted 27 April 2019
Available online 09 May 2019
0160-4120/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
F. Madia, et al. Environment International 128 (2019) 417–429

ongoing to reach a 15% reduction of cancer incidence by 2020 and to

target 2030 SDGs (EU Communication, 2016). Several initiatives have
been put in place over the past two decades following a recommenda-
tion of the Council on cancer screening (EU Council Recommendation,
2003) and the establishment of a European Partnership to support the
Member States in their efforts in fighting cancer (ECIS, 2018; EU
Commission Communication, 2009; EU Parliament Resolution, 2008).
Acknowledging the important contribution that effective chemical
safety assessment has to inform risk management measures and reduce
the burden of cancer, we reflect here on the role of carcinogenicity
assessment in the broader public health context. We take into con-
sideration actual cancer scenarios, the contribution of chemical ex-
posure to the disease, the impact of current EU legislative measures,
and the influence of public health policies. In addition, we report on
current scientific advances in carcinogenicity assessment and their
Fig. 1. Cancer incidence and mortality in 2018. European and Global cancer potential to help the fight against cancer.
incidence and mortality figures. Data are reported as estimated number of in-
cident cases and deaths for all cancers (both sexes, all ages). Data refer to year
2. Risk factors and cancers of most concern
2018. In parenthesis, estimated prevalence (5-year survival from first diag-
nosis). (Global Cancer Observatory, http://gco.iarc.fr/today/home, and ECIS,
https://ecis.jrc.ec.europa.eu/index.php, accessed on 06/11/2018 @ European Cancer is a broad term encompassing many different highly het-
Union 2018). erogeneous but related diseases affecting potentially almost every tissue
in the body (NIH NCI, 2018). While different explanations have been
put forward for the causes and mechanisms of cancer, it is acknowl-
and Wei, 2012; Landrigan et al., 2016; WHO Cancer Report, 2014); 2)
edged that there is a complex interplay of multiple risk factors, which
high urbanisation and dense distribution of aged population, with long-
can contribute at the same time or at different stages over longer time
term exposure to occupational and environmental carcinogens and
frames (Anand et al., 2008).
medicines (EEA Chemicals for a sustainable future, 2018); 3) chronic
From an evolutionary perspective, cancer can be regarded as a
exposure to particulate matter, ozone, benzo[a]pyrene and other pol-
conserved trait across species, typically the result of an adaptive re-
lutants that are above European standard limits and WHO air quality
sponse to rapid changes in the environment (Aktipis and Nesse, 2013).
guidelines which have been linked to significant increase of respiratory
From this perspective, the ecological context of cancer cells parallels
NCD and cancers (EEA Air quality, 2018); 4) the deployment of early
that of the organisms they live in. They respond similarly to: the
detection and screening programs (e.g. prostate or thyroid cancer) that
emergence of new stressors; to increased availability of nutrients; to the
contribute to a documented increase of cancer incidence due to the
allocation of energy to growth at the expense of survival (as re-
detection of precursor lesions (Jönsson et al., 2016; Luengo-Fernandez
production at the expense of health); to cellular defence mechanisms
et al., 2013; Vineis and Wild, 2014).
(e.g. action of the immune system); and to the co-evolution with pa-
Occurrence and survival data show significant disparities in tumour
thogens (Aktipis et al., 2013; Lichtenstein, 2005).
types across European countries; these can be linked to differences in
While cancers cannot be completely avoided, evidence strongly
environmental and occupational exposure, including air pollution level
suggests that susceptibility to the disease can be reduced significantly
differences, lifestyles, demographic factors and to some extent to the
by reducing the impact of several risk factors.
budget that national governments devote to health care (Arnold et al.,
Cancer risk factors that might be largely preventable include bio-
2015; ECIS, 2018; Jönsson et al., 2016; Luengo-Fernandez et al., 2013;
logical agents (infections), exposure to synthetic chemicals through
Vineis and Wild, 2014). For example, Denmark has one of the highest
work or consumer products, and lifestyle factors such as exposure to
incidence rates but spends less on cancer than Sweden, which has lower
sunlight, poor diet, being overweight, tobacco use and consumption of
incidence rates (Jönsson et al., 2016).
alcohol. These risk factors are reported to collectively contribute to the
At international level, the World Health Organization (WHO) has
development of 70–95% of all cancers (Colditz and Wei, 2012; Wu
recognised the burden of cancer on health and the resulting social and
et al., 2016). While the specific contribution from chemicals to cancer is
economic impacts. In 2017, the 70th World Health Assembly of the
difficult to quantify with certainty, a number of estimates have been
WHO adopted a resolution on cancer prevention and control, with a
made. In 2008, Anand and colleagues (Anand et al., 2008), reported the
broad consensus that “Cancer is a growing public health concern which
following relative contributions: diet (30–35%); tobacco (25–30%);
requires increased attention, prioritization and funding” (WHO Assembly
infections (15–20%); obesity (10–20%); alcohol (4–6%); others, in-
Resolution, 2017). The resolution “urges Member States, […], to imple-
cluding pollutants and radiation (10–15%). Similar estimates were re-
ment comprehensive cancer prevention and control programs, including
ported by Belpomme and colleagues and WHO (Belpomme et al., 2007;
management of disease …[…] fostering the development of effective and
WHO Cancer Report, 2014). Colditz and Wei, excluding tobacco use,
affordable new cancer medicines” but also, to enhance the coordination of
proposed that the contribution from chemicals is 4–10% (Colditz and
activities related to the assessments of hazards and risks and the commu-
Wei, 2012).
nication of those assessments (WHO Assembly Resolution, 2017).
Family history and ageing represent instead unavoidable risk fac-
Within the United Nations (UN), the Sustainable Development Goals
tors. For 5–10% of cancer cases, significant correlations with specific
(SDGs) of the 2030 UN Agenda for Sustainable Development are also
inherited genes have been identified (e.g. BRCA1 and BRCA2 gene
relevant. In particular, SDG-3 aims “[…] to ensure healthy lives and
mutations in specific breast cancer types; HPC1 and TLRs in prostate
promote well-being for all at all ages”, includes specific targets to reduce
cancer; MLH1, MSH2, MSH6, APC, PTEN in colorectal cancer) (Colditz
premature mortality from non-communicable diseases by one third and
and Wei, 2012; Wu et al., 2016). With increasing age, stress resistance
“[…] to substantially reduce the number of deaths and illnesses from ha-
decreases as well as the ability to repair cellular and DNA damage.
zardous chemicals and air, water and soil pollution and contamination”
Since this is combined with the cumulative use of pharmaceuticals and
(United Nations, 2015).
exposure to stressors, including chemicals, the vulnerability to cancer
Cancer disease is a central priority of EU health policy and a number
might increase with age. For some types of cancer, such as oesophageal
of initiatives on screening, control and prevention programs are
carcinoma, liver hepatocellular carcinoma, pancreatic adenocarcinoma,

418
F. Madia, et al. Environment International 128 (2019) 417–429

All other cancer sites

27.2 2015; Tosti et al., 2018; WHO Cancer Report, 2014).
Stomach 2.7 The prevalence of lung cancer is attributable mainly to occupational
Non-Hodgkin lymphoma 3.2 exposures but also to air pollution and tobacco use. A higher risk of lung
Pancreas 3.3
cancer has also been associated with chronic pulmonary diseases (Tu
Ca n c e r s it e

Kidney 3.3
et al., 2017).
Melanoma of skin 4.0
Bladder 5.5
Prostate 12.2 3. Chemicals and cancer
Lung 12.5
Colorectum 12.6 Scientific research has led to considerable insights into the many
Breast 13.5 ways exogenous chemicals can adversely affect human health and cause
0 10 20 30 cancer. However, accurately estimating the proportion of all cancer risk
Distribution [%] attributable to chemical exposure remains a formidable challenge.
There are many variables to take into account, including duration of
Fig. 2. Estimated incidence by cancer site in EU in 2018. The chart reports the
exposure, demography, geography, environment, and individual sus-
estimated percentage distribution of cancers in the EU (28 Member States) for
the year 2018, both sexes, all ages. Each bar is proportional to the contribution
ceptibility. This is why the incidence of cancer attributable to exposure
of each cancer to the total. to toxic chemicals has been estimated to be between 1 and 19% (Anand
Source: ECIS https://ecis.jrc.ec.europa.eu, accessed on 03/15/2019 © et al., 2008; Colditz and Wei, 2012; Forouzanfar et al., 2015; IARC,
European Union, 2019. 2018; Kessler, 2014; President's Cancer Panel, 2010).
General estimates from a recent WHO report (Prüss-Ustün et al.,
2016) attribute approximately 20% of all cancers to environmental
pheochromocytoma, stomach adenocarcinoma, bladder and colon
factors, with occupational exposure ranging between 2 and 8% and
cancers, the effect of ageing has been suggested to outweigh other risk
cancers due to chemicals in the environment around 1.5–2%.
factors (Podolskiy and Gladyshev, 2016).
Differences in estimates can be due to study context (target cancer
Despite the high heterogeneity of cancer types, humans are mainly
or target pollutant) or to uncertainties in the collection of data or be-
afflicted by breast, prostate, lung and colorectal cancer. There are also
cause of different approaches to data analysis. For example, the con-
increasing trends in cancers of the stomach, cervix, liver and bladder
tribution of air pollutants to lung cancer has been attributed as follows:
(Rahib et al., 2014; WHO Cancer Report, 2014).
17% to household air pollution, 14% to ambient air pollution, 7% to
In Europe, breast cancer is the most common, with nearly half a
residential radon, 7% to occupational exposure, and 2% to second-hand
million new cases per year. This is closely followed by colorectal, lung
tobacco smoke (Prüss-Ustün et al., 2016).
and prostate cancers, with lung cancer showing the poorest prognosis
Moreover, as recently discussed at a Scientific Committee Seminar
and leading to approximately 20% of all cancer deaths. Prostate cancer
organized by the European Environmental Agency, there has been an
has shown a levelling-off in its mortality rate which is most likely due to
overall underestimation of the potential risk of environmental chemi-
the introduction of early screening for the prostate-specific antigen
cals, the majority of which are less studied. It has been reported in fact
(PSA) biomarker (Fig. 2) (ECIS, 2018; Heijnsdijk et al., 2018; Torre
that there has been a historical bias toward deepening knowledge and
et al., 2015).
providing more information on chemicals with known risk (EEA
The prevalence of these four cancers is not attributable to a single
Chemicals for a sustainable future, 2018). The strongest evidence for
cause although they share some common traits. Notably, these cancers
cancer occurrence associated with chemical exposure is related to oc-
have similar anatomical origin. In fact, their cells derive from the same
cupational settings. In the workplace, characterisation of the environ-
original epithelial cell type (same original germ layer). Epithelial can-
ment, exposure levels, exposure time-frame and the health status of
cers (carcinomas) represent 80–90% of all cancers, which is not sur-
workers can be tracked in a precise and accurate way. Acquisition of
prising since epithelial tissues are the most abundant in the body
such data has led, for example, to the conclusion that lung cancer ac-
(McCaffrey and Macara, 2011). Since epithelia lie at the interface be-
counts for 54–75% of all occupational cancers (Cogliano et al., 2011;
tween the organism and its environment, they are the first to respond to
EU Commission Staff Working Document Impact Assessment, 2016).
any type of insult. Such responses occur in a multi-step process and may
lead to chronic inflammatory pathologies and cancer formation, as
3.1. Chemical carcinogens
observed in the case of colorectal cancer in the gastrointestinal tract
(Madia et al., 2012).
Over the past 40 to 50 years, the International Agency for Research
Although the anatomical origin can influence tumour classification
on Cancer (IARC) has classified over 1000 agents, with the majority
and development, similarities in mutations and signalling pathways
being occupational chemicals and some complex mixtures. The eva-
have been observed. These have been linked to family history or spe-
luations have shown that 50% of them are truly, probably or possibly
cific mutations as in the case of BRCA prostate and breast cancers
carcinogenic to humans, while the remaining 50% are not classifiable
(Agalliu et al., 2009; Rimar et al., 2017; Song et al., 2017) and to
because of insufficient data (IARC, website). The chemical carcinogens
common underlying mechanisms and signalling pathways (e.g. PI-3-
identified by IARC largely overlap with those registered as carcinogens
Kinase/Akt, RTK-RAS, etc.) that are shared across the different cancers
in the European Chemicals Agency (ECHA) inventory of harmonised
(Hoadley et al., 2018; Thorsson et al., 2018).
classified substances (CLP Inventory, C&L), which represent about 3%
Furthermore, compelling evidence has recently linked breast,
(4604 out of 141,823, as on June 6, 2018) of the whole chemicals in-
prostate and colorectal cancers with insulin resistance. This is a pa-
ventory (ECHA, website). This suggests that a significant number of
thologic condition observed in metabolic disorders such as obesity and
chemicals are still in need of thorough review, implying a considerable
type-2 diabetes mellitus and associated immune deregulation to which
demand for testing and evaluation of carcinogenic potential.
both genetic and environmental factors might jointly contribute.
The European Union deals on average with the production of > 300
The environmental factors likely reflect the shift toward unhealthy
million tonnes of chemicals per year, of which 12–15% are classified as
dietary habits typical of industrialised countries, including overeating
Carcinogenic, Mutagenic or toxic to Reproduction (CMRs, harmonised
and consumption of processed food or excessive amounts of nutrient
classification) (Eurostat; EU Report, 2016) (Fig. 3). These include more
supplements, hormones and growth factors. In addition, exposure to
than a thousand chemicals known or presumed to be carcinogenic (Cat
contaminants in the food chain may play a role (Arcidiacono et al.,
1A and 1B) or suspected to be carcinogenic (Cat 2) and that can be
2012; Djiogue et al., 2013; Fontana and Partridge, 2015; Persano et al.,
predicted to induce mutagenic or toxic effects to reproduction (CLP

419
F. Madia, et al.
130
P roducti on vol um e s [%]
120
110
100
90
80
70
2004 2006 2008 2010 2012 2014
[years]
Fig. 3. Chemical production volumes in the EU. Percent variation of aggregated
production volumes, in million tons, of chemicals over years 2004–2016 in the
EU. Chemicals were broken down into five toxicity classes and non-hazardous
chemicals: carcinogenic, mutagenic and toxic to reproduction (CMR) chemicals;
chronic toxic chemicals; very toxic chemicals; toxic chemicals; harmful che-
micals and non-hazardous. These classes are derived from the risk phrases as-
signed to individual substances in Annex 6 of the Dangerous Substances
Directive (amended in 2011), and adapted to the CLP most recent classification
(EU Report, 2016). Data were elaborated from Eurostat (http://Ec.Europa.Eu/
Eurostat/Web/Main/Home): as from 30/01/2018.
800
(6.9%)
Uni que substa nce s [n]
600
400
(22.1%)
(16.2%)
200
0
Cat 1A Cat 1B Cat 2
Hazard categories for carcinogens
Fig. 4. Substances classified as carcinogens. Data retrieved from the CLP in-
ventory. Unique chemicals with harmonised classification for Carcinogenicity
and Mutagenicity, based on CLP/GHS classification of hazard categories for
carcinogens. The inventory contains classification and labelling information on
notified and registered substances received from manufacturers and importers
but it also includes the list of harmonised classifications. In parenthesis: percent
(%) of chemicals with a classification for toxicity to reproduction within each
carcinogen category. https://echa.europa.eu/information-on-chemicals/cl-
inventory-database. Data were extracted on 03/08/2017.
Inventory, C&L) (Fig. 4). In this regard, the legislative system in place
for registration and authorisation through REACH (EC Regulation 1907,
2006), and classification and labelling through the CLP Regulation (EC
Regulation 1272, 2008), has contributed to the identification and
management of the risks linked to the substances manufactured and
marketed in the EU. In addition, several other pieces of EU legislation
including those regulating biocides, pesticides, drinking water, and
occupational safety and health (OSH) have all contributed to the
stricter control of carcinogenic substances.
The implementation of the REACH and downstream sector-specific
legislative measures (Supplementary Table 1) have led to a gradual
decrease of production of highly toxic (chronic) and CMR chemicals
(Fig. 3) (EC Communication, 2018; EU Report, 2016; EU Study, 2017;
EC Commission Staff Working Document, 2018). This reduction may be
partly explained by the increase of chemicals identified as substances of
very high concern (CMRs; Persistent, Bioaccumulative and Toxic sub-
stances - PBTs; very Persistent or very Bioaccumulative - vPvB) and
classified as requiring either specific authorisation or restriction mea-
sures on marketing and use (Article 59(10)) (EC Regulation 1907,
Environment International 128 (2019) 417–429
CMRs 2006). For example, the restriction of substances such as chromium
Chronic toxic (VI), dichloroethane, lead chromates, trichloroethylene and more re-
Very toxic cently decaBDE, PFOA, PFOA-related substances and PAHs has resulted
Toxic in reduced risk for workers and consumers (EU Study, 2017).
Harmful A number of different health indicators are used to estimate the
Non-hazardous positive impact of chemical risk management such as reduced mor-
Total tality, increased survival rates, reduction in direct and indirect medical
costs and increases in worker productivity. These have shown that the
strongest legislative impact has been primarily the reduction of occu-
pational cancers, resulting from reduced exposure to occupational
2016 carcinogens by as much as 7% per year (EU Study, 2017). In relation to
13 well known carcinogens for example, it is estimated that over 1
million deaths from cancer have been avoided (EU Study, 2017). In
general, therefore, one can assume that the risks of occupational ex-
posure to carcinogens are well managed by all the legislative measures
put in place over the last 20 years (Supplementary Table 1).
The assessment of the impact of EU chemicals legislation on en-
vironmental exposure of the general public has been limited by un-
certainties related to data collection, health indicators and confounding
factors. In addition, it is very difficult to describe the causal relationship
between environmental chemicals and cancer disease (EU Report,
2016; EU Study, 2017). The assessments conducted also confirmed the
need for more initiatives to generate information and facilitate under-
standing (e.g. via relevant indicators) concerning human exposure to
environmental chemicals (e.g. from human biomonitoring programs),
and mutagen 1B the carcinogenic properties of chemicals, and the contribution of che-
and mutagen 2 mical exposure to human disease.
not classified as mutagen Specific associations between chemical exposures and certain can-
cers have been recently reported. For example, breast cancer has been
associated with the cumulative exposure to pesticides and other che-
micals (Jeon et al., 2018; Rodgers et al., 2018). Several key studies have
been reviewed, suggesting higher breast cancer risk for exposures
during breast development to dichlorodiphenyltrichloroethane (DDT),
dioxins, perfluorooctanesulfonamide (PFOSA) and air pollutants and,
for occupational exposure, to solvents and other mammary carcinogens
such as gasoline (Rodgers et al., 2018).
Approximately 5% of childhood cancers have also been estimated to
result from environmental exposure to pollutants (Kessler, 2014; Prüss-
Ustün et al., 2016; Roberts and Karr, 2012). To focus on one particular
case in 2013, an eight-year-old Chinese girl was recognised as the
youngest person to get lung cancer due to fine particulate matter via
outdoor air pollution (Kessler, 2014), declared as carcinogenic to hu-
mans by IARC (IARC, 2016).
Concerns have also been reported concerning chronic, low-level
exposure to chemical mixtures, which are considered to be poorly
characterised and yet to be systematically addressed (Goodson et al.,
2015). Notably, in recent years the European Commission, acknowl-
edging that the assessment and management of mixtures is only partly
covered by current legislation, has identified several gaps and areas for
action. A number of initiatives both at research and policy level are on-
going, which are expected to have a strong impact (EC Communication,
2012; Bopp et al., 2018a, 2018b). Ongoing dialogue between the
Commission services, European agencies and scientific experts is fo-
cused on reviewing the current state of knowledge and further elabor-
ating and prioritising policy and research needs (Bopp et al., 2018a,
2018b).
While some information on the effects of chemicals during critical
windows of susceptibility (e.g. development, pregnancy or puberty) can
be extrapolated from a number of available standard regulatory toxicity
studies, no test method exists that involves exposure through the
complete lifespan, from conception to old age, which also covers car-
cinogenicity assessment. Thus, effects undetected during those specific
windows of exposure might still give concern for delayed effects leading
to cancer later in life (such as for endocrine-disrupting chemicals or
neuro- or immuno-developmental toxic chemicals) (Biro and Deardorff,
2013; Grandjean and Bellanger, 2017; Hughes and Waters, 2017;
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Osborne et al., 2015; Vandenberg et al., 2012). Moreover, individual
substances can independently trigger several of the mechanisms of the
carcinogenic process (EEA Chemicals for a sustainable future, 2018;
Kienzler et al., 2016; Landrigan et al., 2017).
3.2. Changes in chemical exposure patterns
Recent discussions suggest that the REACH Legislation, while con-
tributing to reducing the overall risks of chemicals in the environment,
is protecting mainly against highly toxic chemicals in the workplace,
and inadvertently encouraging the introduction of new substances with
unknown properties (EEA Chemicals for a sustainable future, 2018;
Scheringer, 2017).
Indeed, chemical exposure scenarios are changing quite rapidly
both in terms of the amount and diversity of substances (Hendry et al.,
2007) to which we are exposed. Changes in toxicological properties of
chemicals and exposure patterns are predicted to adversely affect both
human health and the environment (EEA, 2015). With regard to car-
cinogens, the proportion of non-genotoxic versus genotoxic carcinogens
in the environment is expected to increase, since scientific knowledge
on DNA reactivity allows industrial chemists to design compounds
without overly reactive moieties. In addition, the manufacture and use
of novel types of substances including nanomaterials, new generation
pesticides and pharmaceuticals (e.g. biologicals, cell and gene thera-
pies) are expected to increase. This raises new challenges for risk as-
sessment and risk management. Testing procedures and regulatory in-
formation requirements will have to be revisited and gaps eventually
filled.
3.3. Limitations of the current carcinogenicity assessment paradigm
prostate, no adequate animal model exists. In addition, for tumours in
the ovary, the human tumours derive from different cellular origins
than those induced by chemicals in rodents. In breast cancer, it has
been reported that mammary gland premalignant lesions in mice do not
parallel human pathological changes (Thayer and Foster, 2007).
Coupled with all these concerns over the scientific relevance of the
animal tests for carcinogenicity, is the strong demand within the EU
(EU Directive 63, 2010) to reduce the use of animals for scientific
purposes and instead to use alternative (non-animal) approaches to
fulfil regulatory testing requirements where possible.
Another important aspect of current practice is that carcinogenicity
testing is rarely conducted under the REACH legislation unless trig-
gered by specific alerts or exposure conditions (i.e. production vo-
lumes > 1000 t/year (EC Regulation 1907, 2006); long-term exposure
and widespread dispersive use; mutagens of category 3 or where there
is evidence of hyperplasia or pre-neoplastic lesions from repeated-dose
toxicity studies). This represents a potential protection gap, especially
for non-genotoxic carcinogens that, when not classified for any other
hazard property and not identified as such in (limited) repeated dose
toxicity studies could go unidentified (EC Regulation 1907, 2006; ECHA
R7a, 2017; Jacobs et al., 2016; Luijten et al., 2016; Madia et al., 2016).
In the case of cosmetic ingredients, for which in vivo testing is
banned (EC Regulation 1223, 2009), the assessment of carcinogenicity
relies on alternative testing approaches only. In the case of new in-
gredients that do not fall under other regulations, an in vitro geno-
toxicity test battery remains the main driver for carcinogenicity as-
sessment. It is worth noting as well that for other sectors, such as
pharmaceuticals, there is the proposal to waive the carcinogenicity
rodent assay whenever sufficient supporting information is available
(Braakhuis et al., 2018; Luijten et al., 2016; van der Laan et al., 2016).

Several groups have long questioned standard regulatory testing
procedures which mainly rely on rodent assays (Table 1), pointing out a
number of drawbacks related to their applicability to assess the po-
tential of chemicals to cause cancer in humans (Heinonen et al., 2014;
Knight et al., 2006; Paparella et al., 2017).
Scientific concerns include the overestimation of carcinogenic ef-
fects due to the typically high doses used in rodent studies and the
uncertainties linked to extrapolation from rodent to humans due to
species-specific biology and chemical mode of action (Cohen, 2017;
Goodman, 2018; Madia et al., 2016). Importantly too, the 2-year rodent
bioassay and chronic toxicity studies do not specifically address the four
cancers of most concern described above since they were originally
designed to cover a very wide range of possible health effects and
cancer types. In addition, the 2-year rodent bioassay has proven in-
adequate to specifically predict hormonally induced reproductive tu-
mours (Thayer and Foster, 2007). For some types of tumours such as
4. Recommendations for adapting carcinogenicity assessment to
meet future needs
The nature of cancer burden and the associated trends, together
with changes in exposure patterns of chemicals in the environment
need to be considered in anticipating how carcinogenicity assessment
should evolve to offer adequate levels of protection to human health.
The contribution of different risk factors, the prevalence of certain
cancers over others, the evolution of the disease and the link to other
morbidities, the exposure to chemicals in occupational or environ-
mental settings, have all to be taken into account in devising cancer
prevention strategies, which include a proper assessment of chemical
carcinogenicity. Consequently, the approaches and test methods in use
in regulatory toxicity testing need to be continuously adapted.
Initiatives are already underway to utilise new data- and knowl-
edge-driven approaches in carcinogenicity assessment, which profit

Table 1
Internationally agreed testing methods for carcinogenicity.
Test OECD test Species/number Objective of the study Duration of the study
method guideline

Carcinogenicity studies
Combined chronic
toxicity/
carcinogenicity studies
Chronic toxicity studiesa
TG. 451 Rats and mice
(50–65/sex/group)
Non-rodents (mainly dog)
(4–6/sex/group)
TG. 453 Rat (10/sex/group) chronic
phase; and (50/sex/group)
carcinogenicity phase
TG. 452 Rodents (20/sex/group) and non-
rodents (4/sex/group)
Observe test animals for a major portion of their
life span for the development of neoplastic lesions
during or after exposure to various doses of a test
substance
Identify carcinogenic and the majority of chronic
effects and determine dose-response relationships
following prolonged and repeated exposure.
Characterise the profile of a substance in a
mammalian species following prolonged and
repeated exposure.
Normally 24 months for rodents. For
specific strains of mice, duration of
18 months may be more appropriate.
Normally 12 months for the chronic
phase, and 24 months for the
carcinogenicity phase.
Normally 12 months but, 6- or 9-month-
studies are also performed.

Internationally agreed testing methods for carcinogenicity. Data were retrieved from the OECD website. The above methods are used by industry and governments
for the regulatory safety testing of carcinogenic potential of chemicals.
a
The chronic toxicity study is not aimed specifically at testing carcinogenicity, but it can be used for early detection of neoplastic lesions (Madia et al., 2016).

421
F. Madia, et al.
from the involvement and cooperation of both scientists and regulators
from different product sectors. The integration of available information
on relevant endpoints, including from epidemiology, traditional and
alternative toxicology test systems, together with novel data streams, is
undoubtedly considered a way forward to address in the short-term the
limitations of the current carcinogenicity testing paradigm (Corvi et al.,
2017).
Here, by broadening the context of regulatory toxicology to include
more human specific cancer disease related-issues we emphasise a
number of elements that we consider instrumental in providing some
options to meet the future needs of carcinogenicity testing.
4.1. Addressing the four most prevalent cancers
One of the limitations of the current carcinogenicity testing para-
digm, based on the 2-year rodent bioassay and chronic toxicity studies,
is the difficulty to properly target the potential of a chemical to induce a
specific type of cancer (Thayer and Foster, 2007). This is because the
traditional animal studies were designed to identify any possible
cancer. On the other hand, specific assessments on a routine basis for
each cancer type are unlikely to be economically and practically fea-
sible, given the huge number of chemicals in need of safety assessment.
As described above, recent cancer trends in mortality, incidence and
prevalence (Bray et al., 2018; ECIS, 2018) reveal that cancers in breast,
prostate, lungs and colon-rectum are the most prevalent. We therefore
recommend prioritising the carcinogenicity assessment of chemicals for
their potential to contribute specifically to the development of these
four cancers. For this purpose, a number of options are available to
address these specific cancers within toxicity testing strategies.
One option is to investigate the role of specific biomarkers that
describe signalling pathways driving carcinogenesis in the tissues of
interest for the four cancer types. The identification of signalling
pathways that control cell progression, apoptosis or other common
hallmarks of cancer are currently used to describe mechanisms and
differences between individual tumours or tumour subtypes (e.g. on-
cogene and tumour suppressor proteins in breast cancer: Ras, c-Myc,
p53; in colorectal cancer: Apc, Mlh1, Mlh2; or prostate cancer: Myc,
Bcl-2, Hpn, PCA-3, P53 etc.). Such information is currently used in
cancer research to identify causes of cancer and potential therapeutic
targets (Sanchez-Vega et al., 2018) but could also be translated to
toxicity studies.
A number of recently developed in vitro and in vivo cancer models,
which provide detailed information on the mechanisms leading to the
different cancers, can be used in regulatory toxicology. We recommend
prioritising the development of models that detect specific traits of the
most prevalent tumours (e.g., genetically engineered in vivo and ad-
vanced in vitro models). For example, cell culture methods for geneti-
cally predisposed breast or colon cancer are already being used in
biomedical research (Janik et al., 2016; Telang and Katdare, 2007,
2011). Also, 3D models (including organoids) are currently being in-
vestigated for their potential to accurately model physiology, shape and
dynamics of colorectal and prostate cancers (Phillips, 2014;
Vlachogiannis et al., 2018; Young and Reed, 2016).
Furthermore, biomarker gene signatures currently in use for early
cancer diagnosis and clinical treatment decisions can be exploited to
prioritise chemicals in need of thorough assessment for a specific cancer
type. Grashow and co-workers (Grashow et al., 2018) have recently
proposed an example of this type of approach. The authors have iden-
tified several occupational and environmental chemical classes that
increase breast cancer risk. However, thousands of chemicals remain
untested for their breast carcinogenic potential. Therefore, the authors
have used biomarker gene kits from clinics to prioritise and curate a
panel of genes which can serve as a biomarker of mammary toxicity and
breast carcinogenesis (Grashow et al., 2018; Rodgers et al., 2018).
Similarly, gene signatures for sub-types of non-small cell lung
cancer (NSCLC) (Shoshan-barmatz et al., 2017) have been recently
422
Environment International 128 (2019) 417–429
described and might be used as biomarkers to screen for potential lung
carcinogens. The advantage of using biomarker gene signatures lies in
their applicability to different test systems: experimental in vivo or in
vitro studies and in vitro High-Throughput Screening (HTS).
4.2. Better use of information on cancer aetiology and evolution in humans
A second option for adapting carcinogenicity assessment to evolving
cancer scenarios is to make better use of knowledge of human phy-
siology and pathophysiology deriving from research on human cancer
biology, clinical studies and human biomonitoring. All these provide
large amounts of relevant data that can inform toxicity studies.
Specific human relevant effects and events involved in the devel-
opment of cancer disease in humans also represent important in-
formation. For example, immune effects, inflammatory events, epige-
netic modifications, hormone alterations, including of the non-pituitary
axis (e.g. Insulin Growth Factor 1, IGF-1) have been clearly identified as
intermediate events in the carcinogenesis process (Jacobs et al., 2016;
Martin, 2013; Villeneuve et al., 2018). New techniques and novel
methods to accurately investigate such events are also becoming
available and can be used to enhance standard toxicity studies (Smith
et al., 2016; Guyton et al., 2018). This means opportunities to design fit-
for-purpose studies based on more human-relevant data.
In this direction, although not overcoming all the uncertainties of
standard in vivo studies, the recent update of standard 28-day and 90-
day repeated dose toxicity studies (OECD TG 407, 2008; OECD TG 408,
2018) and the inclusion of endocrine disruptor assessment into legis-
lation represent another step toward an improved assessment of carci-
nogenicity. These initiatives are expected to have a significant impact
on the identification of endocrine disruptors and eventually those
chemicals with the potential to induce hormone-related cancers (ECHA
and EFSA Guidance Document, 2018). A significant impact is also ex-
pected from the on-going OECD project related to the development of
an integrated approach to testing and assessment (IATA) for non-gen-
otoxic carcinogens based on the inclusion of more human-related ef-
fects (Jacobs et al., 2016).
As mentioned above, increased cancer risk has been associated with
several chronic disorders such as cardiovascular disease, diabetes,
chronic kidney disease, and pulmonary disease (Tu et al., 2017). These
include metabolic disorders that share similar signalling pathways and
risk factors with breast, colon and prostate cancer (Persano et al., 2015;
Vineis and Wild, 2014). Information on the links with those diseases
should also be taken into account to better design testing strategies and
be able to discriminate between chronic effects that may or may not
lead to cancer.
Interactions between chemical exposure and ethnic/cultural back-
ground/diet/life style may also play a role in the manifestation of
various cancer types. For example, in addition to environmental car-
cinogen exposures, a hormone-mediated difference in susceptibility to
breast cancer has been observed among US women of different ethnic
backgrounds, with the Afro-American ethnic group being more sus-
ceptible. A number of studies have also described interactions in the
development of cancer in migrant populations. Asians or South
Americans moving to North America or Europe and acquiring wester-
nised life styles have shown increased cancer susceptibility compared to
their populations of origin; in this context epigenetic modifications
seem to play a key role (Martin, 2013). Additionally, endocrine dis-
rupting chemicals have been reported to initiate or exacerbate obesity,
a cancer-predisposing condition (Karoutsou and Polymeris, 2012).
Research and human epidemiology studies have identified critical
windows of susceptibility that can increase cancer risk (Moirano et al.,
2017; Prins et al., 2008; Rudel et al., 2011), as well as other diseases or
long-term toxicity effects (e.g. neurotoxicity effects). In the case of
breast cancer for example, gestation, early childhood, puberty and
pregnancy may represent windows of susceptibility to environmental
insults (Gopalakrishnan et al., 2017; Rodgers et al., 2018; Rudel et al.,
F. Madia, et al.
2011). However, current animal-based toxicity test guidelines do not
allow the study of carcinogenicity within specific windows of suscept-
ibility. One adaptation in the conduct of in vivo studies is represented
by the choice of the appropriate age of the experimental animal.
However, the use of this option is limited by the lack of human re-
levance and other uncertainties (Thayer and Foster, 2007;
Gopalakrishnan et al., 2017; Rodgers et al., 2018). The use of recently
developed in vitro models of human cancer stem cells (CSCs, iPSCs)
which play a key role in tumour formation (Persano et al., 2015), can
overcome such limitations by providing a means of capturing me-
chanisms of early cancer development and progression (Franco et al.,
2016; Persano et al., 2015).
Finally, we recommend that information on cancer aetiology and
evolution in humans should be also interpreted in light of the impacts of
policies currently in place. Such policies include those relating to
health, nutrition, obesity, smoking or drinking behaviours, and results
from recent EU initiatives, such as those tackling breast or colorectal
cancer or the European Joint Action Innovative Partnership for Action
Against Cancer (ECIS, 2018; IPAAC, 2018). This information is crucial
to better understand the evolution of the disease in the exposed po-
pulation, to interpret the links with other diseases or cancer-predis-
posing conditions and potential toxic effects, and to determine the re-
lative contribution of different risk factors (Martin, 2013). It also helps
to identify the most prevalent specific endpoints or mechanisms that
should be included in the carcinogenicity assessment.
4.3. Use of biomarkers of exposure and human biomonitoring
To address the continuous change of chemicals present in the en-
vironment and evolving exposure scenarios, we recommend furthering
the identification and use of biomarkers of exposure, effect and sus-
ceptibility. Biomarkers give evidence of association between exposure
to specific chemicals and a carcinogenic effect and may provide in-
formation on mode of action. They provide a range of possible mea-
surements from systemic exposure to resulting causal events in the
process of carcinogenesis. The use of biomarkers has been re-
commended by the UK Committee on Carcinogenicity to establish re-
cent exposures to actual or potential carcinogens not only in humans
but also in experimental animals (Committee Carcinogenicity UK,
2013).
Biomarkers of exposure, referring to chemicals or metabolites
measured in human biological media, provide a valuable means of
tracking exposure levels in the general population and in subgroups
with unusual exposures or vulnerabilities to certain diseases including
cancer. Biomarkers of exposure can approximate internal dose and
identify highly exposed groups (Rudel et al., 2014). Data from biomo-
nitoring and biomarkers of exposure can be used as reference-values in
risk assessment or guide the screening of potentially bio-accumulating
chemicals (Neveu et al., 2017; Wild et al., 2013). Also, even if the ex-
posure in occupational settings is typically higher than for consumers, it
represents a relevant source of information on general chemical ex-
posure effects and health impacts. In this context, the information
gathered through the on-going European Initiative HBM4EU is expected
to improve risk assessment by providing better evidence of the actual
exposure of the population to chemicals, along with contextual in-
formation on possible health effects (HBM4EU, 2018). In fact, human
biomonitoring in Europe has relied on well-established national pro-
grams in a number of EU countries (Ganzleben et al., 2017). Human
biomonitoring data measurements are not currently required by the
European Chemicals Legislation (EC Regulation 1907, 2006; ECHA
R14, 2016; ECHA R15, 2016). However, such information is accepted
and considered to give added value in the exposure assessment both for
workers and consumers.
Biomarkers of exposure can also be used to monitor chemical
combination (mixture) effects within changing chemical exposure sce-
narios. For example, a number of ongoing EU research projects are
423
Environment International 128 (2019) 417–429
addressing research gaps in the area of mixture effects, including the
development of joint epidemiological-toxicological approaches for
mixture risk assessment and for prioritising mixtures of concern (Bopp
et al., 2018a, 2018b). Other projects are also expected to be valuable for
carcinogenicity assessment. For example, the ChemDIS-Mixture tool
can be used to identify potential effects of mixture interactions (Tung
et al., 2018).
In addition, biomarkers of effect which can describe a key event
implicated in a carcinogenic mode of action such as genotoxicity,
changes in hormone levels, evidence of cell-specific toxicity (e.g. via
altered proteins or altered gene expression) can be used to characterise
the hazard and be considered as markers of adversity. For this purpose,
the Adverse Outcome Pathway framework is an effective means to
synthesise the relevant mechanistic knowledge in a form suitable for a
regulatory context (Langley et al., 2015; Villeneuve et al., 2018).
Finally, furthering the investigation and use of biomarkers of sus-
ceptibility, acquired or inherited, which describe an individual's sus-
ceptibility to a specific cancer is important to better characterise the
exposed population and eventually to identify individuals at high risk.
For example, different genetic polymorphisms (e.g. overexpression of
oncogenes or loss of function for tumour suppressor proteins) are used
as biomarkers to identify individuals with a predisposition to develop
breast cancer or colorectal cancer (Rothman, 2011). In addition, genetic
susceptibility has been suggested to play a role in one's response to
environmental chemical exposures. The investigation of gene-environ-
ment interaction can help to identify individuals at risk for specific
chemical exposures. Preliminary evidence suggests for example that
genetic variants in xenobiotic metabolism, DNA repair and immune
response can modify the susceptibility to non-Hodgkin-lymphoma
(NHL) following exposure to organochlorines, chlorinated solvents,
chlordanes and benzene (Kelly and Vineis, 2014). This represents an
important area of investigation with strong implications in terms of
both chemical risk assessment and public health.
4.4. A practical approach toward modification of the current paradigm
The actual applicability of the options provided above is supported
by a series of recent studies to evaluate chemicals for their potential to
contribute to breast cancer risk (Grashow et al., 2018; Rodgers et al.,
2018; Rudel et al., 2011; Schwarzman et al., 2015).
In the context of National Initiatives for New Chemicals Screening
and Breast Cancer and Chemicals Policy Programs, a ‘disease endpoint’
approach is being developed. Starting from insights on the breast cancer
aetiology and epidemiology evidence, a detailed analysis of biological
effects of the disease and changes in biological pathways that serve as
early indicators of toxicity has led to the development of tailored me-
chanistic tools able to identify specific breast cancer-inducing traits.
Such new tools, such as the curated genomic biomarker panel for
screening (Grashow et al., 2018) or the protocol for hazard identifica-
tion (Schwarzman et al., 2015) can be fully integrated in the process of
carcinogenicity assessment.
In this case, the public health concern of breast cancer incidence
becomes the starting point to drive the risk assessment and to screen
and prioritise chemicals specifically for that adverse effect. Hence, the
knowledge of specific biological disease pathways drives the sorting of
available and pertinent toxicity studies and where missing, the in-
troduction of new data streams. This type of approach is suitable for
screening and prioritising chemicals of concern in need of thorough
assessment but is also applicable to different regulatory frameworks
where for example, the hazardous properties of chemicals must be
identified and reported on registration (e.g. REACH). Here, carcino-
genicity information can be generated by the use of ad hoc studies,
sorted on the basis of the hallmarks of cancer and description of the key
characteristics of carcinogens and organized in the form of Integrated
Approaches to Testing and Assessment (IATA) (Jacobs et al., 2016). We
suggest therefore that such an approach represents an effective yet
F. Madia, et al.
flexible means of carcinogenicity assessment that can accommodate
different public health priorities and regulatory contexts.
5. Conclusions
The rising rates of cancer incidence and prevalence identified by the
World Health Organization are of serious concern. The scientific ad-
vances of the past twenty years have helped to describe major prop-
erties of cancer disease, enabling therapies that are more sophisticated
and effective. However, it has become clear that the management of
relevant risk factors can also significantly reduce cancer occurrence
worldwide. Public health policy actions cannot be decoupled from en-
vironmental policy actions, since exposure to chemicals through air,
soil, water and food can contribute to cancer and other chronic dis-
eases. Furthermore, due to the increasing global trend of chemical
production including novel compounds, chemical exposure patterns are
foreseen to change, posing increasing demands on chemical safety as-
sessment, and creating potential protection gaps. The safety assessment
of carcinogenicity needs to evolve to keep pace with changes in the
chemical environment and cancer epidemiology. A number of tools are
available or under development to more accurately assess the carci-
nogenicity endpoint. However, future strategies for assessing carcino-
genicity should also take into account the prevalence of certain cancers,
the contribution to the disease of different risk factors, the study of
relationships between chemical exposure and risk factors, the disease
aetiology and links with other disorders. In addition, changes in che-
mical exposure patterns and exposed populations are also critical con-
siderations. A more holistic approach to carcinogenicity assessment
would focus on the chemicals of highest concern, and use human-re-
levant testing methods to guide the most appropriate risk management
measures.
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.envint.2019.04.067.
Disclosure statement
Declarations of interest: none.
Acknowledgments
We are thankful for our reviewers Ciaran Nicholl, Sandra Caldeira
and Raquel Carvalho from the Health and Society Unit of the JRC's
Directorate for Health, Consumers and Reference Materials for their
critical evaluation of the manuscript.
Funding sources
The preparation of the manuscript was supported by European
Commission‘s Joint Research Centre institutional funding only.
List of abbreviations
Akt Protein kinase B (PKB)
APC Adenomatous Polyposis Coli gene
BRCA1-2 breast cancer type 1-2 susceptibility genes
C&L CLP Inventory of harmonised classified substances
CLP Classification, Labelling and Packaging
CMRs Carcinogenic, Mutagenic and toxic for Reproduction
CSCs Cancer stem cells
ECHA European Chemical Agency
HPC1 Hereditary Prostate Cancer 1
HTS High-Throughput Screening
IARC International Agency for Research on Cancer
IGF-1 Insulin Growth Factor I
iPSCs Induced pluripotent stem cells
MLH1 Lynch syndrome/Hereditary Non-Polyposis Colorectal
424
Environment International 128 (2019) 417–429
Cancer (HNPCC)
MSH2 Human MutS Homolog 2
MSH6 MutS Homolog 6
NHL non-Hodgkin-Lymphoma
NSCLC Non-Small Cell Lung Carcinoma
PI-3-Kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase
PSA prostatic-specific antigen
PTEN Phosphatase and Tensin Homolog
REACH Registration, Evaluation, Authorisation and Restriction of
Chemicals (REACH) Regulation
RTK/Ras Receptor tyrosine kinase (RTK) pathway
small GTPase SDGs, Sustainable Development Goals
TLRs Toll-like Receptors
UN United nations
WHO World Health Organization
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