by Dr. Lang Tran
The management of health risk is a complicated process. The method for risk
management consists of two fundamental elements:
1. The steps to be taken (to achieve the specific objectives);
2. the rationale which justifies the choice of the steps in
In this short article, we will outline the method for managing the potential
health risks arising from exposure to engineered nanoparticles (ENP).
Risk to health is a product of both the intrinsic Hazard of a material, and
the level of Exposure. We will describe the processes involved in Hazard and
Exposure assessment in order to undertake an assessment of risk. Finally, we
will outline one possible approach for managing risk.
To assess the hazard of a substance is to evaluate its inherent toxicity.
Fundamental to the science of toxicology is the dose-response relationship. For
particles in general, exposure tends to be via inhalation. However, because of
their extensive use in industrial processes and commercial products, for
engineered nanoparticles (ENP), exposure can be via inhalation, ingestion or
Once internalised, it has been shown that ENP may be translocated from the
primary organ of entry into secondary organs. This evidence has presented a real
challenge to toxicologists, because risk assessment must now be focused on the
dose-response relationship of the most sensitive body organ rather than solely
on the organ through which ENP enter the body.
Ultimately the assessment of hazard must be related to humans. In toxicology,
the most frequently available models for toxicity testing are animal based and
may be either in vitro or in vivo. Typically, initial investigation of the dose
response relationship between ENP and potential toxicity is undertaken using a
body of in vitro tests - selected to be valid (i.e. relevant) to the target
Of primary importance is the range of doses which do not cause a significant
effect (i.e. statistically significant response level in comparison to the
control). The data generated by these tests can then be used to establish a
quantitative relationship between the different physico-chemical characteristics
of the ENP and the respone elicited. This process is the basis of
Quantitative-Structure-Activity-Relationship (QSAR) modelling.
Those tests undertaken within dose-response assessment of the ENP must
undergo two further steps:
1. validation; and
Validation is undertaken to ensure that the tests are reproducible, assuming
that the test protocols are followed exactly - usually achieved via a round
robin aproach between investigators. Verification on the other hand, is to
ensure that the results of those in vitro tests carried out correspond to actual
observations obtained from animal experiments (or human clinical situations).
The verification of in vitro results therefore usually requires the use of
limited in vivo animal experimentation, with which there may be associated
ethical issues. As a result, it is essential that these in vivo tests are well
designed and focused, in order to satisfy the ethically considerations laid out
by the 3Rs principle of refinement, reduction and replacement.
Extrapolation between in vitro and in vivo results requires a judicious
choice of both dose administered and dose rate. Recent findings from Oberdörster
et. al. demonstrate good concordance between in vitro and in vivo results in the
pulmonary system when response is described as response per cm2.
Another important issue is distribution of ENP in different target organs, as
this is essential to understanding target organ dose and choice of reference ENP
material in toxicity tests. Indeed, choice of a suitable reference nanomaterial
is of key importance to benchmarking and comparative toxicity between ENPs.
In summary, for hazard assessment it is essential to study the dose-response
relationship in context of the most sensitive organ/system the ENP is likely to
reach. Ascertaining the physico-chemical properties of ENPs which drive their
toxicity, and the range of dose with no observed adverse effects are essential
to undertake a meaningful hazard assessment. Figure 1 presents these and other
key aspects of hazard assessment.
Figure 1. The Hazard and Risk Assessment
Regardless of how hazardous a material is, without exposure there is no risk.
Assessment of exposure is therefore of equal importance to understanding of
hazard in the risk assessment process. Exposure to humans is possible - both
directly and indirectly - throughout the entire life cycle of an ENP, from
handling in the workplace during production, consumer use and final disposal. At
each stage there is a potential for direct exposure to both humans (as either
workers or consumers) and the environment (e.g. soil, water and air). Within the
environment, the properties of the ENP are likely to be altered by their
surroundings, and hence their fate and behaviour in these media is difficult to
predict. In addition, ENP may come into contact with different species in the
environment, enter the food chain and thus eventually provide an additional
indirect source of exposure to humans.
Therefore, important considerations in assessing exposure to ENP are the
likelihood of major accidental exposure scenarios (e.g. explosion or major
spillage into the environment) and methods for exposure monitoring (including
personal sampling and the use of novel biomarkers of exposure which can detect
ENP in blood, urine and sputum). Figure 2 summarises the various exposure
scenarios for humans.
Figure 2. Exposure
Risk Assessment and Management
Although hazard assessment may yield useful in vitro and/or in vivo results,
it is risk assessment which places these findings in the human context. The risk
assessment process extrapolates these in vitro / in vivo results to humans,
achieved by application of a range of uncertainty factors which attempt to
compensate for inter-animal variations and inter-species differences. This
approach may lead to over-estimation of risk and as a result setting of
unrealistic exposure limits.
A more promising approach may be mathematical modelling of the
exposure-dose-response using the available experimental data. Once established,
such models can be extrapolated to a human context and used to estimate the
level of exposure which does not initiate an adverse effect for a chosen
endpoint. This is known as the Derived No Effect Level (DNEL). The advantage of
this mathematical modelling approach is that uncertainty can be included
readily, most frequently achieved via use of the Monte Carlo simulation.
Assessment of risk involves comparison of the calculated DNEL with the total
exposure in humans estimated through the exposure assessment process, if the
total human exposure is found to be greater than the DNEL then there is a risk
of a development of the adverse effect. Figure 1 summarises the risk assessment
The next step in Risk Assessment is Risk Decision - the rational decision to
accept or reject risk which must be made following the risk assessment. This
decision will be based on the impact of calculated health risk on both the
social and economic infrastructure. If the risk is small in comparison to the
social-economics trade-offs, then the risk may be acceptable. If not, the risk
is perceived as too great and the risk rejected.
If the risk is rejected, then it must be suitably managed - this is the
process of risk management. The two fundamental processes in risk management are
Risk Control and Risk Transfer. Risk Control involves exposure monitoring, the
use of protective clothing, and communication to stakeholders via for example
standard operating procedures, guidance and dialogue using different media such
as TV, internet and open forums..
Another important process is identification of human exposed cohort for a
health surveillance exercise. Risk Transfer involves adoption of appropriate
insurance for the calculated risk. The main challenge, in this instance, is
being how to price appropriately insurance to cover for those health risks
arising. Figure 3 summarises the process of Risk Management.
Figure 3. Risk
In this short article, the method for risk assessment and management of
exposure to ENP has been outlined. One main limitation of the exemplar approach
is that it relies heavily on the control of exposure; a step which may be
difficult as for example in practice the mass airborne concentration of ENP can
be very low and thus difficult to control. However, since ENP are man-made, it
will be possible to re-design and produce them without those physico-chemical
properties identified as having adverse effects. Needless to say, these
redesigned ENP must still fulfil their original industrial needs. Ultimately, it
is this hazard reduction method which is key to a responsible development of
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