Nanotechnology and Risk Assessment

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); and
  2. the rationale which justifies the choice of the steps in (1).

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.

Hazard Assessment

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 dermal contact.

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 organs.

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
  2. verification

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 Process.

Exposure 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 Assessment Rationale.

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 process.

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 Management Procedure

Conclusion

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 sustainable nanotechnologies.