The Australian Pesticides and Veterinary Medicines Authority (APVMA) published a draft Risk Analysis Framework in November 2011 (see http://www.apvma.gov.au/consultation/public/2012/risk_analysis_framework.php). While publication of the Risk Analysis Framework should improve transparency about the way decisions are made within APVMA and should help all stakeholders to understand what data the regulator needs to enable it to make its decisions, lack of clarity within the Framework results in the document failing to clarify what data are required by the regulator.
An example of the lack of clarity in the draft Risk Assessment Framework is the statement that toxicology data are assessed to determine ‘if possible, a “safe” level of exposure in animals. This is known as the no-observed effect level (NOEL)’. The Framework also claims that ‘international best practice’ is used for risk assessments.
The Framework, as published leads me to ask if the APVMA really means it uses international best practice or does it really require the use of practices (such as the NOEL) that have been largely abandoned by other regulators? Without clarity, an applicant cannot decide whether data relied upon by other regulators to approve substances will be be usable by APVMA to assess the risk posed by a substance or not.
The issue of the NOEL is not the only instance of a lack of clarity within the Framework. But it is an important example. So what is wrong with the NOEL?
The NOEL theoretically looks at any observed effect. The NOEL is the dose at which the administered substance causes no effects, irrespective of whether the effects are adverse or not. Some effects may have no real significance and are not used for regulatory decision-making. For this reason, the NOAEL or No Observed Adverse Effect Level is now more commonly used for such decision-making.
Consider this example. Ivan Petrovich Pavlov once did experiments in which he rang a bell when dogs were to get food. Eventually, the dogs would start to drool whenever the bell was struck (because they associated the bell with food). We know drooling, or salivation, is an important response to food. It starts the digestive process. However, it would not normally be considered an adverse effect — but it is an effect.
Assume if, instead of striking a bell, Pavlov sprayed some chemical into the air. The animals might start drooling every time they smelt the chemical, expecting food to be served. Would we consider drooling in this case to be the type of effect that should drive regulatory decision making, i.e. determine if the chemical is allowed to be sold or not? Should we say a chemical is not allowed to be sold or used because it causes drooling in this experiment?
If the regulator requires the dose or concentration at which No Effects are observed to be used for regulatory decision making, the drooling would have to be considered an effect and would need to be used as the basis for decisions such as whether a chemical can be supplied or not. In this case, to select a “safe” level for the chemical, as defined by the regulator, we would need to look for a concentration of the chemical that does not cause drooling. The highest rate or concentration of the chemical tested that does not induce drooling would be termed the NOEL.
In contrast, the NOAEL would recognise drooling is an effect but not an effect that is significant in relation to regulatory decision-making. Decisions about whether to permit supply or use of the chemical would need to be made on adverse effects.
What effects are “adverse” is something that competent toxicologists must determine. The NOAEL is the highest dose tested that did not produce any toxicologically significant effects, as determined by the expert toxicologists. APVMA has access to highly competent toxicologists (and other experts). However, the Framework, as written, could reduce the ability of these experts to use their expertise in regulatory decision making.
Some people may argue no competent regulator would make a decision simply because, say, an animal started to drool because of some odour. This may be true but we know regulators are not always the final decision makers, e.g. legal action may result in courts requiring a strict interpretation of terms used in the Framework.
To avoid problems in the future, I believe it is essential that the Framework use precise terminology.
On the other hand, if APVMA really does not want experts to have the flexibility to use their expertise in decision making, and does require them to use the NOEL rather than the NOAEL or other appropriate criteria, then APVMA should not mislead stakeholders by claiming it uses ‘international best practice’.
In my view, the Risk Analysis Framework must be amended to ensure there is clarity as to what is expected. Only then will the regulated community, the regulator and other stakeholders have common ground for determining what is and what is not acceptable.