ISO TR 22019:2019 pdf free.Nanotechnologies – Considerations for performing toxicokinetic studies with na nomaterials.
5 Importance of toxicokinetic information for risk assessment of nanomaterials
5.1 General
Toxicokinetic studies are important to obtain insight in the toxicologically relevant target organs that can be considered more closely in the safety evaluation and risk assessment of NMs and/or NPs. Furthermore, information might be obtained on relevant exposure durations (e.g. acute, chronic) to be applied in toxicity studies based on the persistence of the NP over time. Finally, such information is essential to enable more reliable extrapolations over species, time and exposure routes and can be used for grouping, read-across and waiving.
5.2 Possible use of toxicokinetic information
For dissolved substances, legislation differs in the requirement for providing kinetic information, also between countries, but most often this information is not required by legislation[.lfil. However, toxicokinetic knowledge is essential for various purposes in the current risk assessment approach based on animal tests:
— to predict systemic exposure and internal tissue dose (correlate given dose with target dose);
— to know whether a test, such as a genotoxicity test in bone marrow or sperm, is relevant (does the substance reach these tissues?);
— to perform route-to-route extrapolation (see e.g. Reference [12]);
— to perform high-to-low-dose extrapolation or to select appropriate doses (see e.g. Reference iiaj and [.19]);
— to verify human relevance of test results from animals (i.e. perform interspecies extrapolation; e.g. Reference [2-0]);
— to enable extrapolation in time for accumulating substances, as animal tests do not cover an entire human lifetime, while accumulation can lead to increases in concentration in a tissue that continues lifelong (e.g. Reference [21]).
When avoiding animal tests as much as possible and performing a risk assessment based mostly on in vitro test results, as envisioned by the 3Rs principle[221, kinetic information becomes even more essential. In vitro tests do not provide for the totality of the toxicokinetics of a whole body, as animals do: the absorption in the intestines, for example, is not included in an in vitro test with liver cells. Thus, in vitro test results need to be supplemented with kinetic information using kinetic models, in a process named in vitro in vivo extrapolation (IVIVE).In addition, toxicokinetic information provides insight into potential target organs and organ burden that might ultimately result in toxicity. This allows for improved selection and design of hazard studies, e.g. waiving a certain systemic study if absorption and accumulation of the substances are known not to occur, or adding additional analyses to a study that are relevant to identified target organs.
These considerations are valid for both NMs and soluble substances. Specific for non-degradable NMs is that there is a higher potential for accumulation. In the case of accumulation, determination of the kinetics is of greater importance for the correct estimation of a health risk, as an extrapolation in time needs to be made. This is valid for accumulating NMs just as much as it is for accumulating substances. Internal (or target tissue) concentrations are therefore better dose metrics for risk assessment purposes than external doses.
Specific for NMs is also that they have a distinct distribution pattern, with high proportions in organs of the mononuclear phagocytic system (MPS) notably in the liver and spleen. Such information can, for example, warrant special attention for potential effects on liver and spleen cell populationsl2.111Z31.
Due to the many forms in which NMs can occur or be produced, of which testing all would require a large amount of resources, grouping is of high interest for NMs. Recent papers on possibilities for grouping of NMs describe kinetic parameters as essential pieces of information on which to base group formation and justification: degradation (including dissolution), distribution and potential bloaccurnulation or persistence and distributionIZ4IIZ5lIZfil. Dissolution is actually a physico-chemical parameter that also is dependent of the local environment (e.g. water, buffer or (simulated) body fluids), but can also be seen as a kinetic parameter. The rate of dissolution/degradation provides insight in the toxicokinetic behaviour of a NM. Until dissolution occurs, the kinetics of NMs are governed by the particulate nature of the NMs, whereas after dissolution the (dissolved) ions or molecules determine the toxicokinetics. Distribution studies are needed to assess if and to which extent the different NMs show distribution to the same target organs, as part of a scientific justification for grouping, and to assess if the same hazards can be considered. Accumulation is a kinetic parameter, which is not measured directly, but is determined by all other (more basic) kinetic parameters, i.e. absorption, distribution, and elimination.ISO TR 22019 pdf download.