- Active substances
- Risk for the consumer
- Risk for the operator, bystander, worker and local residents
- Formulation (plant protection product)
- Labelling of the formulation
In toxicology, tests are carried out to ascertain all possible toxic effects of both the active substance and the plant protection product before it is placed on the market. A product may be hazardous, but that does not yet mean that humans or animals are at high risk. Indeed, the risk is the hazard multiplied by the probability that a person is exposed to this hazard.
risk = hazard x exposure
That is why, in addition to any hazard assessment, an assessment of the exposure will also be made.
Based on toxico-kinetic studies, it is ascertained how the substance is absorbed and excreted, and what the degradation products are, generally among rats, but if there are more sensitive species, also among mice and dogs. On the basis of this, it is determined which species need to be tested more extensively. Rats and dogs are always tested as a precaution.
In the first instance, the acute intoxication hazard is determined: the toxicity via single exposure through all absorption channels (mouth, skin, lungs).
Using these data, the toxicity after repeated exposure is determined: sub-acute (28 days) and sub-chronic (90 days - 1 year).
During the assessment, the long-term danger is further investigated, at various levels. Studies are carried out on rodents during their complete lifespans, in other words 1.5 - 2 years, during which time any carcinogenic potential of the active substance is investigated. Furthermore, a reproduction study is conducted, covering 2 generations of rats, as well as studies which look into the effect on development (teratogenicity) on rats and rabbits.
Depending on the type of substance, studies may also be requested which cover hazards for the nervous system (among adults or offspring), or possibly the endocrine system or immune system.
Finally, the substance's capacity to influence the genetic material of mammalian cells is also assessed, both in-vitro (on bacteria, cell lines and human blood cells) and in-vivo (on complete organisms).
For substances which can damage genetic material, an acceptable level of exposure can never be determined, according to current understanding. In addition, substances which are clearly carcinogenic, or cause birth defects or fertility problems in humans, are not deemed to be safe for use.
Such substances can never be considered for approval. A possible exception can be made for carcinogenic or reprotoxic substances for which the exposure would be insignificantly small.
It is essential that all toxicological tests are obligatorily carried out under Good Laboratory Practice conditions, which is a quality system which offers the most guarantees for the correct conduct of the study, and also a precise, accurate and controllable reporting of the study results. In addition to the studies carried out by the applicant, all relevant published articles and books from public scientific literature is consulted as an additional source of information.
It can be reasonably assumed that all of these studies allow the risk of the products to be correctly assessed, both during the most critical phases and for a person's full lifespan.
A crucial element on the toxicological assessment is that for every substance and each critical phase, a threshold value can be established, below which no harmful effects are expected.
From the above-mentioned test animal research data, reference doses (which dose is safe?) are inferred, which are then compared with estimated exposure levels (to what dose am I exposed?) in food and the surroundings.
Risk for the consumer
The government assesses the risks of short and long-term exposure to active substances through food.
With regards to long-term exposure, it is determined what quantity of the relevant substance a consumer can consume every day for their whole life without a significant risk. This 'Admissible Daily Intake', or ADI is expressed in milligrams per kilogram of bodyweight per day. From the toxicological studies, the evaluator will infer the highest level of exposure, for which no harmful effects were found in the most sensitive test animals. The ADI is calculated from this by applying uncertainty factors which compensate for the differences between animals and humans, and the differences between humans individually. An uncertainty factor of at least 100x is applied to the obtained results, but higher factors might be considered on a case by case basis.
The evaluator will then make an initial, overall estimate of the quantity of active substance which a consumer can ingest via food. For the sake of safety, the worst case situation of exposure is assumed, in other words a high consumption and high content of pesticides. Consumption by, inter alia, small children (the most sensitive persons) are considered separately. This estimated level of exposure is compared with the level which is deemed to be safe. The substance can only be approved if the exposure remains lower than the ADI.
On the other hand, it is also possible that a food item, consumed during one or more meals, contains more of the active substance than what can be consumed on average. This is especially important for pesticides with high acute toxicity. In order to protect consumers from peak exposure, the Acute Reference Dose (ARfD) is also determined for these substances, in addition to the ADI. This is the quantity of a given substance which a consumer can ingest during one meal, or one day, without significant risk. The method of determining an ARfD is the same as that for establishing an ADI, with the difference that for the ARfD, it will be based on an acute and not a chronic toxicological adverse effect.
Risk for the operator, bystander, worker and local residents
In addition, during the authorisation procedure for plant protection products, exposure (via inhalation or skin contact) is studied of operators and workers who have various tasks such as handling treated crops, but also bystanders and local residents. To this end, empirical exposure models are used which are based on exposure results after spraying, for example in an open field or in greenhouses. It is important to stress that both the models and the underlying data are currently being reviewed, in order to refine the estimates of human exposure.
In order to allow us to estimate whether the exposure is acceptable, the internal exposure levels in humans are compared with the so-called AOEL reference value (Acceptable Operator Exposure Level), which is obtained on the basis of the highest, most relevant dose for which no effect was observed in the repeated oral toxicity study, and for which a sufficiently high safety factor is still taken into account (as with the ADI or ARfD). In order to determine internal human exposure to the plant protection product, the level of dermal absorption of the formulation (both the concentrate and the diluted product) is determined for each product based on in-vivo tests on rats and/or in-vitro tests on the skin of humans and/or rats.
Models are also developed to estimate the combined effects in foodstuffs with residues from different plant protection products.
This will eventually also be possible for aggregated exposure, in other words exposure via various channels: through food, surroundings and work-related exposure. Most evaluators assume that the currently-used safety margins are so wide that the 'combined' exposure will be acceptable for human health in the vast majority of cases, especially since the quantities of sprays have been revised downwards in recent years, and by combining substances (to prevent resistance), individual doses per treatment are lower.
Before being authorised for the market, all plant protection products (formulation = active substance + auxiliary substances) are subject to a number of tests (identity, physico-chemistry, toxicology, ecotoxicology, fate in the environment, human exposure, efficacy), depending on good agricultural practice, which is specific to each Member State of the European Union, given the differences in soil characteristics and climate. Provided that a comprehensive toxicology data package already exists at the level of the active substance, testing at the product level is limited to acute effects, irritation (skin, eyes) and over-sensitivity of the skin. In this way, the toxicological properties of all the components of the plant protection product are taken into account (some co-formulants are no longer authorised on this basis, and also on the basis of other, currently known toxicological data at the substance level).
Moreover, the European authorities are currently developing more complex assessment strategies to take into account possible cumulative or synergistic effects, in order to better hedge against the risks of so-called 'cocktail effects'.
In this respect, it can be observed that it is scientifically possible to measure ever lower concentrations of residues in food and the environment. However, it is wrong to conclude from this that these residues would by definition be harmful to health. Indeed, mention is made in some publications of the possible adverse effect of given substances, or combinations of substances in "low doses". There is however no consensus regarding the alleged toxicity of "low doses". An effect which is observed at "extremely low doses" may only correspond with a normal physiological reaction without adverse consequences. Before making any statements in this respect, it is expedient to develop assessment strategies for cumulative effects (as previously described), and study their impact, not just for plant protection products, but for all environmental pollutants (ambient air, household products, additives and food contaminants, biocides, etc.). However, such a cumulative risk assessment is extremely difficult, given the level of detail and the complexity of the toxicological dossiers. Moreover, the current knowledge of toxicological operating mechanisms, as well as the possible complex interactions with all other possible substances to which we are exposed, are insufficient to draw meaningful conclusions.
In conclusion, we can state that the federal evaluators are aware of the uncertainty of low-dose effects and cumulative effects, where special attention is given at the European level, in particular by the EFSA. If necessary, the assessment strategies will be adapted based on scientific developments. This concerns not only problems related to plant protection products, but chemical substances in general.
However, the current assessment is based on the (still) generally accepted principle of dose-response. Knowing that a large margin of safety exists between the doses to which users and consumers may be exposed and the reference doses (safe doses), it is justified to conclude that - under the correct conditions of use - a substance or even a combination of substances does not entail unacceptable risks.
Labelling of the formulation
Thanks to the efforts of standard-setting and inspecting government institutions, safety for the user is guaranteed. However, users, both professional and house and garden users, must be correctly and comprehensively informed about the possible hazards of the products. Based on all the studies (toxicology, physico-chemistry and ecotoxicology), standardized hazard and precautionary statements, and hazard pictograms are imposed. Each authorisation certificate contains all the legal information which authorisation holders must incorporate into their commercial label. Both the label and the safety sheets (which must be supplied with every product for professionals) are the cornerstone of this hazard communication.
It is the responsibility of government, authorisation holders, distributors and sellers to clearly communicate this to users. Conversely, it is the responsibility of users to use the product correctly, and to protect themselves and all parties concerned, in order to keep all risks as low as possible.
The extensive assessment dossiers are the basis for safely handling plant protection products. Nonetheless, this does not mean that no a posteriori assessment takes place. Both at the European level and national level, active substances and formulations are assessed every 10 years (first review) or 15 years (subsequent reviews). In addition, every possible harmful effect which is reported in scientific literature (including relevant epidemiological data) or in reports of studies by the phytopharmaceutical firms themselves, is closely monitored by the competent authorities. Relevant information which is gained from incidents with plant protection products may also be useful in this respect.
Any new and relevant adverse effect, both with regards to human health and the environment, is assessed and can result in an authorisation being revoked.