The Australian Pesticides and Veterinary Medicines Authority (APVMA) establishes and uses technical policies to ensure its risk assessments of pesticides and veterinary medicines are scientifically robust, fit-for-purpose and consistent with international best practice.
No-observed-effect level (NOEL) and no-observed-adverse-effect level (NOAEL): use in animal health risk assessments
Since November 2016, the APVMA has adopted the use of the terms no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) in evaluations to consider the safety of agricultural chemicals and veterinary medicines.
This decision was taken to harmonise with other regulatory bodies (e.g. Joint FAO/WHO Expert Committee on Food Additives, Joint FAO/WHO Meeting on Pesticide Residues, European Food Safety Authority, US Environmental Protection Agency, Canadian Pest Management Regulatory Agency).
The following definitions, based on that described in Principles and Methods for the Risk Assessment of Chemicals in Food (2009), WHO Environmental Health Criteria, No. 240 have been adopted:
- No-observed-adverse-effect level (NOAEL): greatest concentration or amount of a substance, found by experiment or observation, which causes no detectable adverse alteration of morphology, functional capacity, growth, development, or lifespan of the target organism under defined conditions of exposure.
- No-observed-effect level (NOEL): greatest concentration or amount of a substance, found by experiment or observation, which causes no alteration of morphology, functional capacity, growth, development, or lifespan of the target organism distinguishable from those observed in normal (control) organisms of the same species and strain under the same defined conditions of exposure.
The APVMA noted that it had previously used the term NOEL in a manner consistent with the definition as described in 'Principles for the safety assessment of food additives and contaminants in food (1987)', WHO Environmental Health Criteria, No. 70.
This definition includes the statement that the NOEL results in no detectable, usually adverse, alteration of morphology, functional capacity, growth, development, or lifespan of the target.
The APVMA notes that its decision to adopt the definition of NOAEL from WHO Environmental Health Criteria No. 240 did not entail any change in its evaluation practice and was merely harmonising the terminology used to differentiate between observed effects and observed adverse effects. Hence, this decision had no impact on any of the previous human health risk evaluation conclusions made by the APVMA.
All WHO Environmental Health Criteria monographs are available online.
Worker health and safety risk assessments undertaken by the APVMA
Occupational exposure arising from mixing/loading or spraying pesticides comes primarily through skin contact and/or by inhalation. The first consideration for a WHS risk assessment is to identify all toxicological hazards in studies where the treatment conditions in experimental animals are similar to the route of human professional exposure (i.e. dermal and inhalational, 5 days per week and hours per day).
Most toxicological databases for pesticides submitted to regulatory agencies include a 21- or 28-day (or in some cases 13 weeks) rat or rabbit dermal toxicity study, which may be appropriate for consideration of occupational exposure. In the absence of such studies, a route-to-route extrapolation using a repeat-dose oral toxicity study will need to be considered. If a gavage or dietary administration study is used for the WHS assessment, then a dermal absorption factor will also need to be identified.
In most cases, a detailed dermal exposure risk assessment will not be necessary if no systemic toxicity was observed in the repeat-dose dermal toxicity study at a limit dose of 1,000 mg/kg bw/day. Portal-of-entry effects in such studies, e.g. dermal irritation, can be considered in conjunction with the acute toxicity effects of the product formulation. If systemic toxicity observed in oral dosing studies indicates adverse effects that were not tested in the standard dermal study (e.g. developmental or neuropathology), then a dermal study investigating these effects, or a suitable oral dosing study for route-to-route extrapolation should be used. Another important consideration is whether steady-state has been achieved. This occurs when plasma concentration is in equilibrium with its elimination. If the pharmacokinetic data in laboratory animals suggests that plasma steady-state concentrations have not been achieved within the duration of the dermal study, then dermal toxicity data is not recommended. In such cases, a suitable duration oral dosing study will need to be selected for a route-to-route extrapolation.
For most pesticides, dermal exposure is the most important consideration for determining occupational risk. However, for certain volatile pesticides such as fumigants or when used in confined spaces, e.g. for pest controllers it is necessary to consider the inhalational risk. In such situations, it is appropriate to use short-term inhalational studies as the comparator. In such situations, it is necessary to convert the repeat dose inhalational exposure expressed in mg/m3 (or mg/L) in the laboratory animal study to an equivalent oral dose (expressed as mg/kg bw/day) to determine a margin of exposure with normal use patterns.
For most pesticide application scenarios specific exposure data (e.g. mixer/loader and applicators) are not available. In such situations, the APVMA will routinely determine the dermal and inhalational exposure using the exposure calculators. The most appropriate calculator based on the proposed use pattern will be selected.