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Abstract
When building the novel public mammalian toxicokinetic database (MamTKDB) we collected and included 3927 elimination half-lives (elimt1/2) for 1407 xenobiotics in various species (rat, human, mouse, dog, monkey, rabbit, cattle, pig, sheep, guinea pig, hamster, horse and goat) with specification of compartment (whole body, organ/tissue, cell type, medium) studied. Here we describe and analyse the collected data in MamTKDB 1.0. Most elimt1/2 are for humans and rats and their data differ in some ways: whereas the rat data are mainly for pesticides, the human data are mainly for pharmaceuticals and environmental contaminants. There are also differences in types of compartments studied and in metabolites followed: human elimt1/2 are mainly whole body based (i.e. based on blood plasma or excretion), animal data are additionally for various organs/tissues, cells or media. Contrary to human studies, animal studies regularly administrate radiolabeled (e.g. 14C) substances and distribution of both parent and eventual metabolites are followed, measuring the radioactivity. In rats, substances had been given through single, preconditioning or repeated administration. Single administration studies dominated, but repeated studies generally had longer elimt1/2 than single or preconditioning studies for which elimt1/2 were similar. Repeated administration studies should better ascertain steady state conditions throughout the body, a process involving time-dependent tissue loading, and the data show that for most substances, repeated studies are required to address bioaccumulation potential. About 65% of the substances in MamTKDB 1.0 fulfilled the octanol–water and octanol–air partitioning-based screening criteria (log Kow > 2 and log Koa > 5) for further bioaccumulation assessment and/or testing, and most of the substances with long elimt1/2 in both humans and rats fulfill these criteria. Of note, however, there are also many chemicals with log Kow > 2 with intermediate or short elimt1/2. Per- and polyfluoroalkyl substances (PFAS) stand out in that they often have log Koa < 5. Rats are poor toxicokinetic test models for perfluoroalkyl acids (PFAAs) for which pigs (and possibly mice) elimt1/2 data resemble those of humans better. Perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonic acids (PFSAs) of similar molecular weight had similar elimt1/2 in the species tested. For polychlorinated biphenyls (PCBs), elimt1/2 increases with the degree of chlorination in humans. In relation to other compartments, blood plasma/serum had among the shortest elimt1/2 in rats and often underrepresent elimt1/2 in tissues. Rat data were divided into 38 compartment (tissue or media) types out of which 20 had sufficient data for correlational tests. In general, there was a strong degree of correlation of rat elimt1/2 in-between most compartments, but there were also exceptions. Surprisingly, the correlation between brain and white fat was relatively weak. Interestingly, several substances or their metabolites bound to haemoglobin in red blood cells. MamTKDB 1.0 allows investigation on how certain chemical characteristics influence elimt1/2 and is a promising database for assessment of bioaccumulation potential.
Highlights
Guaranteeing that a foreign chemical does not magnify within a food chain or accumulate in any of the many organs/tissues, cell types and structures in our bodies, is an important task since bio concentration and biomagnification increase the risk of toxicity
Since lipophilic chem icals tend to bioaccumulate more than hydrophilic ones, substances are first screened based on their octanol-water partition coefficients (Kow)
Elimt1/2 data from the Biocides) or POP label (REACH) Candidate List of substances identified as PBT, very Persistent and very Bioaccumulative (vPvB) or persistent organic pollutants (POPs; e.g. environmental con taminants) under the Stockholm convention, as well as some polyfluoroalkyl substances (PFAS) (perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonic acids (PFSAs) that are perfluoroalkyl acids (PFAAs)) from registration dossiers under the REACH Regulation, published at ECHA’s website, were collected
Summary
Guaranteeing that a foreign chemical (xenobiotic) does not magnify within a food chain or accumulate in any of the many organs/tissues, cell types and structures in our bodies, is an important task since bio concentration and biomagnification (both covered under the concept of bioaccumulation) increase the risk of toxicity. Hazard and human risk assessment of chemicals is mainly based on rodent data since testing potentially bioaccumulating and/or toxic substances in higher species than the rat (which is the preferred species in regulatory guidelines) can be ethically questionable. Chemicals with similar partitioning properties may have different bioaccumulation potential due to biotransformation (McLachlan et al, 2011) and excretion/egestion dif ferences. Halogenated chemicals such as polychlorinated bi phenyls (PCBs, lipophilic) and per- and polyfluoroalkyl substances (PFAS, often dual hydrophobic and hydrophilic surfactant characteris tics) have the capacity to remain chemically stable against biodegra dation or other processes such as oxidation or hydrolysis (persistence; see (ECHA-term)), and bioaccumulate in humans
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