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01 May 2012

Nanoparticles: Dealing with the shifting sands

by Dr Michael Maxwell, Benjamin De Campo

Companies must proactively engage with emerging evidence of risk.

As is often true with new and rapidly developing fields, such as the field of nanotechnology, conflicting data and opinion are commonplace.

Trying to discern a true signal of toxicity from a false positive and to make reasonable decisions on product safety in the face of these shifting sands is a complex but critical obligation for manufacturers and suppliers.

Background

Nanotechnology is a relatively novel field of science that is dedicated to creating and exploring uses for particles in the nanoscale (having one or more dimensions of 100 nanometres or less), otherwise known as “nanoparticles”.

Nanoparticles have enormous promise and are likely to lead to quantum leaps in progress in fields as diverse as medicine and pharmaceuticals, agriculture, engineering and materials chemistry.

However, it is well understood in the scientific community that nanoparticles may yield unpredictable hazards, because previously well-understood molecules often behave very differently physically, chemically and biologically, on the nanoscale.

This may have repercussions for those tasked with the responsibility of managing such hazards.

This article sets out a number of recent developments on scientific and legal fronts which highlight how dynamic product safety considerations can be.

Emerging science on nanoparticles Zinc oxide and titanium dioxide

Zinc oxide and titanium dioxide have long been considered safe and are currently used in a wide range of consumer products, including food, dermatological products and new generation sunscreens. However, recent developments have called into question whether nanoscale zinc oxide and titanium dioxide are safe in all circumstances.

A 2011 study in Biomaterials, one of the world’s top journals, showed for the first time that zinc oxide nanoparticles are able to enter human cells and cause

DNA damage (genotoxic). The mechanism of DNA damage remains unknown. DNA damage is a well recognised precursor to cancer, as well as reproductive toxicity and birth defects.

Evidence of this nature can be particularly problematic because it is widely considered that there are no safe thresholds for DNA damage, subject to the nature of exposure, and injuries such as these are highly emotive.

Carbon nanotubes

Carbon nanotubes are small, durable carbon fibres and are used in a vast array of items due to their strength and light weight. They are used in various automobile components, household items and sports equipment.

As with any fibre-like structure, there has always been a theoretical possibility that carbon nanotubes could pose an asbestos-like inhalation hazard leading to diseases such as mesothelioma. Whether this ultimately proves to be the case will depend on many factors including the likelihood that people would be exposed by inhalation to carbon nanotubes of similar dimensions to asbestos and whether those fibres have the kind of physical and chemical properties that could promote fibrosis and carcinogenesis.

Recently, as with zinc oxide and titanium dioxide, there has been an emergence of evidence of possible toxicity associated with certain types of carbon nanotubes. For example, in June 2011 the American Journal of Pathology published a study which reported that, when instilled into the pleural cavities of mice (the site of mesothelioma development), long carbon nanotubes were not cleared as readily as shorter ones and were capable of causing acute inflammation, leading to progressive fibrosis on the parietal pleura — a recognised precursor to mesothelioma.

Putting the science in context

Whilst studies like these provide important, robust evidence on fundamental “basic” science, they are not epidemiological or clinical in nature and are far removed from demonstrating actual human toxicity. Nevertheless, they are supportive of a hypothesis of toxicity which could either evolve into a certainty or be proved incorrect as the science develops. They may be sufficient to support a reasonable suspicion of human toxicity, depending on the circumstances.

In science, Bradford Hill criteria are typically applied to assess causal relationships. There should be robust evidence to demonstrate things like a strong and consistent association, temporality, a dose-response relationship, biological plausibility and reversibility.

The law also has a reasonably strong regard for these criteria, but they are not definitive and simply form part of the “strands of a cable” that a court will consider. There are numerous examples of cases where causation findings have been made supported by only a few of these criteria that arguably did not advance matters beyond a possibility.

To date, the science on the toxicity of nanoparticles such as carbon nanotubes, nanoscale zinc oxide and titanium dioxide has largely focused on biological plausibility. Data to inform the other Bradford Hill criteria remains either unknown or equivocal. However, in the absence of other circumstantial evidence either supporting a causal link, or discounting other plausible causes, that is not to say that it might not suffice to clear any causation threshold.

Importantly, the latency of malignant disease can run into decades, meaning that if there is toxicity associated with certain nanoparticles, it may not be revealed in epidemiological studies for quite some time yet.

Timeframes of this magnitude can also significantly complicate issues around the quality of available evidence, particularly of exposure and any efforts made to assess or respond to potential risks.

Recent developments regarding causation

The emerging evidence of genotoxic effects by certain nanoparticles raises interesting causation issues, particularly in light of two recent judgments of the High Court in Amaca v Ellis [1] and Amaca Pty Ltd v Booth.[2]

Ellis was a case where the plaintiff developed lung cancer allegedly caused by periodic low level occupational exposure to asbestos, in circumstances where he had been a smoker for 26 years.

Ellis succeeded at trial and by majority of the Full Court of the Supreme Court of Western Australia. The case was successfully appealed to the High Court on the sole issue of causation.

The high point of the plaintiff’s evidence was that, based on epidemiological evidence to which the High Court had substantial regard, his smoking alone was 67% likely to be the cause of the cancer whereas asbestos alone or in combination with smoking was at most 23% likely to have been the cause (the remaining 10% was attributed to other potential factors).

Faced with the proposition that a 23% chance ought to be considered a material contribution sufficient to establish causation, the High Court allowed the appeal holding that it must first be shown that the asbestos exposure was “in fact” a cause of the plaintiff’s cancer, before considerations of material contribution should be entertained.

It was insufficient to show that inhalation of asbestos merely increased the risk, or was a possible cause, of the cancer. A 23% chance did not tip the balance of probabilities.

Several commentators have noted that, prima facie at least, this judgment makes it difficult for plaintiffs to prove that they contracted a disease with numerous potential causes (such as cancer), in circumstances where that disease was most likely caused by something that cannot be attributed to the conduct of a defendant (such as lifestyle factors and genetics). Prior to Ellis, there was (in our experience) a perception that it could suffice to show that a defendant’s conduct materially increased the risk.

Booth, on the other hand, arguably makes things simpler for plaintiffs in cases where a product causes a signature disease.

Booth sued brake linings manufacturers on the basis that he contracted mesothelioma from exposure to brake dust containing asbestos, liberated whilst working as a motor mechanic.

The High Court specifically addressed whether the Court of Appeal erred in law by approving the tribunal’s decision that causation could be established by reference to a small increase in risk, including in circumstances where the epidemiological evidence relied on by the defendants showed no increased risk of mesothelioma amongst motor mechanics.

The High Court held that it was open for the tribunal at first instance to disregard the epidemiological evidence on the basis that it was flawed and to find that other factors supported an overwhelming inference of causation. Key factors were the acceptance of not insignificant exposure to asbestos from brake linings and acknowledgement that mesothelioma is caused only by asbestos.

Critically, it was also open to the tribunal to find that the defendants increased the risk of mesothelioma above background by 10 and 20% and that this was not, in the circumstances of the case, sufficient to preclude a finding of material contribution.

Potential implications

For those concerned with the possible toxicity of nanoparticles and relevant developments in the law it is clear that things are moving rapidly, such that the situation now is very different to what it may have been only a couple of years ago. To illustrate:

1. Although much remains uncertain about whether nanoparticles can cause disease, in the form used in consumer products, there have been novel and significant developments that represent a clear signal that such toxicity is possible.

In our experience developments like these, when looked at with the benefit of hindsight, are often viewed (or painted) as watershed moments where emerging risks first became obvious and affirma¬tive action should have been taken.

2. The bar has been set high for those defending allegations that they exposed a plaintiff to a hazard that results in a signature disease. Further evidence supporting a link between carbon fibres and mesothelioma could be particularly significant.

3. Ellis provides significant comfort that evidence of an increased risk of harm may not in itself suffice to support a causal finding, particularly where there are multiple possible, or more likely, causes. It also strengthens Australia’s continued divergence from the UK on the relevance of “material contribution” to legal causation.

4. As Booth illustrates, whilst courts continue to grapple with how epidemiological evidence ought to inform causation, they appear more comfortable having regard to sometimes scant or flawed epidemiological evidence in support of a causal link, particularly at first instance, rather than to rely on it to refute one.

Striking a balance

Manufacturers and suppliers owe a duty to take reasonable care to prevent their products from causing harm to downstream users. Although this is a trite proposition, it is often problematic to strike the right balance in practice.

The regulatory environment is an important factor and evidence that exposures were below relevant standards will help a defendant resist allegations of breach of duty. But it does not end there. Large companies, in particular, are often better resourced than the government departments tasked with developing regulatory guidelines and standards. Companies must proactively engage with emerging evidence of risk. When developments like those described above occur, they can ill afford to sit back and wait for guidance from these agencies.

It is critical that companies ensure their understanding and communication of potential risks to health from their products is up-to-date and appropriate. This is relatively straightforward for well characterised products. It is much more difficult in cases where the scientific knowledge is in a state of rapid flux.

This article was first published in the Australian Product Liability Reporter, May/June 2012

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[1] Amaca v Ellis (2010) 263 ALR 576; 84 ALJR 226; [2010] HCA 5; BC201000970. [back]

[2] Amaca Pty Ltd v Booth (2011) 283 ALR 461; 86 ALJR 172; [2011] HCA 53; BC201109716. [back]

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Clayton Utz communications are intended to provide commentary and general information. They should not be relied upon as legal advice. Formal legal advice should be sought in particular transactions or on matters of interest arising from this communication. Persons listed may not be admitted in all States and Territories.