CURRENT GAPS ON PHYSIOLOGICALLY-BASED KINETIC (PBK*) MODELING

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access in the MAK-Collection for Occupational Health and Safety (MAK Commission, 2021). The testing of analytical accuracy and comparability, respectively, can be performed by:

 the analysis of certified reference materials (CRM) for BM* parameters and/or  the participation in an external quality assurance scheme (EQUAS) for BM* parameters.

Certified reference materials are characterized by a metrologically valid procedure for one or more analytical parameters engaging several well-experienced laboratories, accompanied by a certificate that provides the parameter’s level, its associated uncertainty, and a statement of metrological traceability. The most important bodies, which offer such CRMs, are National Institute of Standards and Technology in the US (NIST) (NIST, 2021) and Joint Research Center of the European Union (JRC) (JRC, 2021). However, the number of BM* parameters, which are covered by CRMs, is low.

External quality assessment schemes for the determination of chemical elements (mainly metals) in human biological material are available in several countries. However, the supply of EQUAS for BM* parameters of organic hazardous compounds is marginal. EQUAS, which offer the proficiency testing of organic BM* parameters internationally, are provided by the Centre de toxicology du Québec (CTQ, 2021), hosted by the Institut National de Santé Publique du Québec (INSPQ), Canada) and the German External Quality Assessment Scheme (G-EQUAS, 2021, provided by the Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine of the University of Erlangen-Nuremberg, Germany).

Current gaps on physiologically-based kinetic (PBK*) modeling

PBK* modeling simulates the concentration development over time of parent compounds and its metabolites in one or several body compartments, which depends on the routes and rates of absorption, protein binding, distribution within the body, metabolism, and excretion (ADME*) (OECD, 2021). In occupational risk assessments, a PBK* model can also be used to:

 Understand the importance of the various routes of absorption e.g., inhalation, skin uptake, or ingestion, which will help in developing exposure reduction strategies (e.g., ventilation for inhalation).  Assess systemic exposure after peak exposures (Cmax) as well as after chronic exposures (AUC), and thus, help in describing the relationship between external and internal exposure e.g., linear or non-linear relationship and possible accumulation.  Estimate target organ doses from exposures that can be compared to mechanistic in vitro concentration-response relations.  Extrapolate tissue dosimetry: from high dose to low dose, route-to-route, inter- and intraspecies.  Calculate the excretion rate and fractions, such as urinary fraction excreted (FUE) that can be directly used to develop human biomonitoring guidance values, such as OBLs*.  Estimate external exposure associated with human biomonitoring data (i.e., exposure biomarker concentrations) (reverse dosimetry)

Basic toxicokinetic parameters are needed to create PBK* models. These are obtained from in vivo, in vitro and in silico studies, which add uncertainties but provide valuable a priori information on individual ADME processes that altogether over time determine the toxicokinetics (e.g., absorption rate constants, protein binding, tissue-blood partitioning, metabolic breakdown described e.g., with Km and Vmax) ((Bessems et al., 2014); (Paini et al., 2021); (OECD, 2021)).

Currently, there are few PBK models publicly available, but the database is expanding rapidly. In vivo human toxicokinetic data are based on highly regulated controlled human volunteer exposure experiments (e.g., in exposure chambers) or on detailed air and dermal exposure monitoring in the workplace with aligned sampling of blood or urine. Both approaches are rather costly and need thorough medical-ethical evaluation compared to in vitro testing or testing in vivo with animals. Currently, some

OCCUPATIONAL BIOMONITORING GUIDANCE DOCUMENT © OECD 2022