The EU chemicals strategy for sustainability (CSS) (EC 2020b) sets policy goals regarding
future ambitions for the safe use and management of chemicals and aims at “chemicals
[to be] used more safely and sustainably, promoting that chemicals having a chronic
effect for human health and the environment—substances of concern—are minimised and
substituted as far as possible, and phasing out the most harmful ones for non-essential
societal use, in particular in consumer products”. To achieve this goal, the EU chemicals
strategy lists several areas requiring future actions with potential consequences
on procedures of chemical regulations currently in place.
The CSS is motivated by public concerns and scientific findings regarding the potential
adverse impacts of chemicals on the environment and human health. It has been intensively
discussed within the scientific community. In many reviews, the CSS received positive
feedback regarding its goals and ambitions. For instance, the CSS was considered as
“the first regional framework aiming to address chemical pollution in a holistic manner”
(van Dijk et al. 2021) or it was appreciated that “prevention and reduction of pollution
[was] on the same political level as the protection of climate and biodiversity” (Conrad
et al. 2021). However, certain aspects of the CSS were more critically commented,
such as the use of terminology (zero pollution, non-toxic, toxic-free) or the lack
of a strategic plan how to implement the zero pollution goal (Herzler et al. 2021;
van Dijk et al. 2021).
Here, we particularly respond to the opinion expressed in a guest editorial by members
of the Federal Institute of Risk Asssement (BfR) of Germany (Herzler et al. 2021)
and a supportive letter to the editor (Barile et al. 2021). Herzler et al. (2021),
in addition to the critical assessment of terminology, expressed specific concerns
that the CSS would negatively affect current risk assessment procedures. They argued
that current schemes of risk assessment are sufficiently science based and performing
generally well with regard to the goal of protection of human populations from chemical
impacts. The editorial further denies that there is sufficient scientific evidence
to justify additional regulatory measures as suggested by the CSS, and criticises
its focus on hazard-based assessment of chemicals and their potential mixture effects.
We provide a different, but also science-based perspective to the CSS. We consider
the CSS primarily as a policy statement that asks for science-based approaches to
meet the challenges of its implementation. Progress in protecting human health and
the environment from undue chemical impacts requires a dialogue of regulatory agencies
with scientists, and other stakeholders, taking into account past experiences as well
as scientific advances. The CSS thus provides an opportunity to revise, modernise,
and improve current hazard and risk assessment procedures based on sound science and
pursuing ambitious goals. In this respect, we would like to complement the view of
Herzler et al (2021). As it is beyond the scope of this letter to provide an in-depth
review of the scientific literature, we rather aim at fostering a constructive and
forward-looking scientific debate for best implementation of the CSS goals. We thereby
will focus on the following aspects:
Terminology of a non-toxic environment and the role of hazard versus risk assessment.
Evidence for sufficient protection of human health regarding chemical exposure by
existing regulation.
Evidence for mixture effects and the need to incorporate mixture toxicity in chemical
regulation.
Fostering the scientific debate to consider and address worries of the population.
Terminology of a non-toxic environment and the role of hazard versus risk assessment
The CSS terminologies “zero pollution”, “non-toxic” or “toxic-free” are not self-explanatory
and are not defined unambiguously. This may lead to misunderstandings that hamper
the implementation of the CSS goals. This issue was previously identified by a CSS
opinion paper indicating that such terminology was rather “reflecting the opinion
of the society, as many Europeans are concerned about the environmental impact of
chemicals present in everyday products” (van Dijk et al. 2021). The CSS, however,
also states that chemicals should be” produced and used in a way that maximises their
contribution to society including achieving the green and digital transition, while
avoiding harm”. This implies that zero pollution may not be the same as zero exposure.
In this line of thinking, van Dijk et al. (2021) proposed that a toxic-free environment
should be interpreted as “an environment in which all chemicals can be emitted as
a result of human activities, but in low concentrations so that no adverse effects
to organism occur”. The definition of van Dijk et al. (2021) is also in line with
common text-book terminology of exposure science and toxicology considering the dose
of a chemical as relevant for its classification as a pollutant or toxicant.
Chemical risk assessment is typically based on the assumption that human and environmental
exposure to hazardous chemicals can be predicted and exposures to dangerous levels
can be avoided. In contrast to risk assessment, a hazard-centred assessment (i.e.
an assessment based on the intrinsic capacity of a chemical to elicit adverse effects)
can be useful in cases where little exposure information is available and prospective
assessment is required. This is already current practice in certain regulations; prominent
examples are the PBT (persistent, bioaccumulative, toxic) assessment and the classification
of compounds as SVHC [substances of very high concern—carcinogenic, mutagenic or reproductive
toxicity (CMR) or endocrine disrupting chemicals (EDC)] in REACH. The precautionary
principle of EU chemical regulation is the major rationale to base certain regulatory
decisions on hazard assessment alone if long-term effects cannot reliably be predicted.
For persistent chemicals, a widespread environmental pollution can lead to accumulation
in biota. Once in the environment, persistent chemicals cannot be removed, and, hence,
this compound property justifies a hazard-based assessment. For SVHCs such as EDCs,
the risk of health effects at even low doses and the uncertainty of predicted exposures
may be considered too high. Consequently, the classic approach of comparing exposure
levels with predicted no-effect concentrations in environmental and derived no-effect
levels in human health risk assessment may not be appropriate. There are options to
improve hazard-based assessments: for instance, a hazard-based assessment may be considered
in a first-tier approximation which provides a scientific incentive to identify and
select appropriate tools, including alternative, non-animal testing approaches, for
better characterisation of such compounds. This has been discussed, e.g. for endocrine
disruption (Natsch 2021).
A hazard-based approach could also be sufficient when discussing the replacement of
compounds for which health risks have been identified—to avoid regrettable substitutions
by compounds with similar properties (Zimmerman and Anastas 2015). This is of particular
relevance for persistent chemicals that may accumulate eventually to hazardous concentrations.
Finally, a hazard-based assessment is also relevant in the context of sustainable
circular use of chemicals to avoid that hazardous chemicals are unintentionally recycled
into new articles resulting in unexpected human exposure (Wang and Hellweg 2021) as,
e.g. demonstrated for bisphenols used in thermal paper, which is recycled to a wider
range of paper products (Liao and Kannan 2011). The ambition for a circular economy
as established in the Circular Economy Action Plan by the European Commission (EC
2020c) may further help to avoid the exposure to additional hazardous chemicals in
products.
Evidence for sufficient protection of human health regarding chemical exposure by
existing regulation
In traditional toxicology apical end points, such as survival, growth or number of
offspring represent the main end points are to estimate the potency of a chemical
to cause adverse effect and to calculate a risk with respect to an expected exposure
condition. With regard to these apical end points, it may seem tempting to consider
the increase in life expectancy or the growth of the world populations as possible
indicators of successful chemical risk assessments as Herzler and colleagues (2021)
argue. Indeed, from the perspective of the increase of our standard of living, health
care, improved sanitation and nutrition, an impact of chemicals on human health seems
less obvious. But studies with twins suggested that environmental—including exposure
to chemicals—rather than genetic determinants—constitute the major cause for a range
of chronic diseases (Rappaport 2016). The Lancet Commission on pollution highlighted
the principal contribution of pollution on health, as expressed by an estimated 9
million premature deaths worldwide in 2015 (Landrigan et al. 2018). To a large extent,
in about 7.8 million, these pollution-associated premature deaths were attributed
to air pollution (particles, ozone) or unsafe water sanitation. Exposure to chemicals
not related to air pollution was associated to more than a million premature deaths.
However, to which extent chemical exposure via consumer products, food or drinking
water affect health is less clear. The WHO and others proposed that various sources
of chemical exposure need to be associated with negative health outcomes (Naidu et
al. 2021; Prüss-Ustün et al. 2011; WHO 2016). Potential human health effects due to
exposure to chemicals have, for instance, been discussed for neurodevelopmental disorders
(Bennett et al. 2016), obesity (Mohanto et al. 2021) or male reproductive health (Foresta
et al. 2018; Pollard et al. 2019; Wu et al. 2022).
In modern toxicology and health sciences, it is well established that humans are exposed
to a large number of chemicals whereby their effects on health are often uncertain.
Chemicals may impact on the health status of organisms at concentrations that are
below those causing consented adverse apical effects. However, addressing and quantifying
the association of exposures with the prevalence of common and non-communicable diseases
is still a major challenge for research. This is illustrated by the example of obesity.
For obesity, about two decades of gene wide association studies could only associate
40–70% of the risk for developing elevated BMI to a genetic background (Locke et al.
2015), leaving 30–60% unexplained. Environmental factors like plasticisers, which
do affect the differentiation of adipocytes, are suspected to play a role. In several
metastudies (Goodman et al. 2014; Ribeiro et al. 2019), however, no clear results
were found, leaving the question to which degree plasticisers contribute to the aetiology
of obesity on the population level open and thus supporting the demand for further
investigations.
Acknowledging the challenge in associating chemical and disease, in our view, is not
equal to denying any role, but rather may call for precautionary approaches until
the safety of chemicals can be ascertained. Novel science-based approaches are needed
here, to quantify whether and to which extent chemicals contribute to disease outcomes.
For instance, integration of exposure assessment, epidemiological evidence and experimental
approaches can be used to establish links between exposure and negative health outcomes.
This was shown in a recent study (Caporale et al. 2022) that established mechanistic
and correlative evidence for an association of in utero exposure to mixtures of endocrine
disruptors and learning disabilities in children.
An extended focus on health implications, diseases or non-apical effect proxies also
call for development, testing and application of new approach methods (NAMs) in the
widened screening and assessment of chemicals. NAMs comprise computational, omics
approaches and alternative test systems, of which the end points are conceptually
linked to molecular initiating and key events of adverse outcome pathways. There is
an increasing demand for application of NAMs, not only motivated by the intention
to reduce animal testing, but also by concerns of weak predictivity of established
animal test models. Moreover, there is a need to increase the capacity of chemical
testing (Fentem et al. 2021; Parish et al. 2020) to keep up with chemical innovation.
It has been argued that the increasing rate and diversity of production of chemicals
exceed societies’ ability to efficiently conduct safety-related assessments and monitoring
and thus transgress the safe operating space of the planetary boundaries for novel
entities (Persson et al. 2022). One can argue that application of NAMs with increasing
automation has the potential to overcome these limitations, so that testing capacity
will not remain a bottleneck. The scientific challenge for the application of NAMs
is their interpretation within regulatory frameworks. The following questions have
to be answered for regulatory implementation: (i) What can be regarded as sufficient
evidence from NAM-based observations to infer a risk of adverse health effects? (ii)
How do NAMs perform in comparison to other pragmatic approaches proposed for regulation
such as the threshold of toxicological concern (TTC)? and (iii) How can we identify
and select suitable NAMs and define regulatory thresholds for restriction of use or
banning of chemicals? The upcoming European Initiative “European Partnership for Chemicals
Risk Assessment under Horizon Europe (PARC)” with its composure of science-oriented
institutions from the regulatory and public research sphere offers the unique opportunity
to serve as a framework to develop and evaluate novel concepts for NAMs-based assessments
useful for regulatory decision making (EC 2020a).
Evidence for mixture effects and the need to incorporate mixture toxicity effects
in regulation
A recent analysis of public inventories estimated approximately 355 000 chemical that
have been registered for production and use, with approximately 69 000 chemicals in
commerce (Wang et al. 2020). The production of chemicals has doubled from 2000 to
2015 (Persson et al. 2022) and is expected to double again from 2015 to 2030 (EC 2017;
UNEP 2019).
These sheer numbers support that exposure of environmental organisms and humans to
chemical mixtures requires accelerated consideration in the assessment of chemicals
(Escher et al. 2020). There is experimental long-standing proof-of-principle evidence
that mixture exposure can provoke combined effects, even if concentrations of individual
compounds occur below their individual effect thresholds (Altenburger and Greco 2009;
Kortenkamp et al. 2009). Mathematical and toxicodynamically founded models were developed,
supporting and explaining the experimental findings (Kortenkamp et al. 2007; Rider
et al. 2018).
Furthermore, lessons learnt in ecotoxicology could be instructive. Monitoring the
species abundance in our freshwaters has indicated that the impact of chemical exposure
in the environment is larger than expected and that apparently the current approach
for prospective risk assessment may not have been sufficient (Liess et al. 2021; Malaj
et al. 2014). Also, despite prospective chemical risk assessment and measures under
the European Water Framework Directive to improve the status of environmental quality,
many surface waters were assigned a moderate to bad ecological status. Among other
factors, this failed good status was largely attributed to chemical pollution (EEA
2018; Lemm et al. 2021).
One may dispute the way how chemical mixtures are considered in chemical regulation
and whether the use of a mixture assessment factor is a universal or the optimal solution
for a specific case. Yet, the application of safety factors is an accepted regulatory
practice in accounting for uncertainty in other areas such as cross-species, or exposure
duration extrapolation. The CSS provides a mandate to develop and improve assessment
of chemicals with regard to mixture exposure. Central to improve mixture assessment
is an improved exposure assessment to identify relevant mixture exposure prospectively.
For retrospective assessment and monitoring, comprehensive assessment of human exposure
to mixtures using advanced technologies of chemical analysis has been just begun,
and more systematic assessment of the human exposome supported by advanced detection
technologies will likely demonstrate even more complex exposure situations than currently
considered in risk assessment (Huhn et al. 2021). Alternatively in the future, one
may use a whole-mixture approach, where mixtures are extracted from (human) samples
and their effects quantified with high-throughput cell-based bioassays (Vinggaard
et al. 2021). We agree that the estimation of the contribution of chemicals to diseases
in humans is not an easy task given the importance of intrinsic factors such as genetic
predisposition and transgenerational effects or socioeconomic factors, nutrition,
air quality, access to green space, physical activity and many more. Hence, research
to understand the effect of mixtures and appropriate consideration of mixtures within
chemical regulations is needed and has been called for by various EU scientific advisory
boards (SCHER 2012) almost a decade ago.
Fostering the scientific debate to consider and address worries of the population
The EU chemical sustainability strategy states that “84% of Europeans are worried
about the impact of chemicals present in everyday products on their health, and 90%
are worried about their impact on the environment”. The editorial of Herzler et al.
(2021) criticises that the concerns may partially be subjective, lacking scientific
evidence, and hence should not drive decisions on chemical regulations. In our perspective,
the CSS represents primarily a policy document, which by its nature also considers
the actual risk perception of European citizens for health impacts of chemicals. However,
the mandate defined by the CSS sets the state for intensified discussion between the
regulatory agencies and related scientific research institutions in Europe for scientifically
defined improvements of hazard and risk assessment. As outlined above, there is also
scientific evidence for (potential) impacts of chemical pollution on human health,
albeit the exact magnitude of the contribution may often not be known. Therefore,
the CSS should be considered as a political mandate and a motivation to close knowledge
gaps, effectively communicate new findings to the public and improve regulations minimising
the risk of chemical exposure for human and environmental health.
Conclusions
We have evidence of a multitude of chemicals being present in the environment and
in our bodies and that mixture exposure indeed matters. This knowledge needs to be
deepened, and the quantitative contribution of chemicals to compromised health should
be better described and translated into regulatory action. As indicated in a scientific
opinion paper of the German Federal Environmental Agency (Conrad et al. 2021), the
CSS goals may be considered as a moving target. For increasing scientific evidence
and improved method for detection and assessment of chemicals, development of new
technologies require innovative regulatory, technological and societal reactions.
We should be flexible and prepared to take up the scientific challenges and collaborate
productively with regulatory institutions to address the identified challenges and
modernise chemical risk assessment. This is also in line with the concern of many
scientists that chemical pollution and the wide range of adverse effects on human
and ecosystem health demand additional efforts on a global scale (Brack et al. 2022;
Wang et al. 2021). We see the CSS as a European strategy that, in concert with other
initiatives, may open new opportunities to minimise hazardous chemical pollution and
thus risks to human health and ecosystems.