Biotransformation Rate Research Articles

Stereoselective profiling of methamphetamine in a full-scale wastewater treatment plant and its biotransformation in the activated sludge batch experiments

The stereoselective biotransformation of methamphetamine (METH), as a chiral compound, during biological treatment in wastewater treatment plants (WWTPs) is often ignored. In this study, a non-racemic form of METH was detected in the raw influent of a full-scale WWTP, with S-(+)-METH as the predominant enantiomer. Stereoselective biotransformation of METH in favor of S-(+)-METH occurred in anaerobic/anoxic and aerobic processes, resulting in the detection of R-(-)-METH as the only enantiomer in the secondary sedimentation tank. To evaluate the stereoselective biotransformation of METH in an activated sludge system, controlled laboratory experiments were conducted under aerobic and anaerobic conditions. Different stereoselective enrichment was observed in a racemic METH batch experiment at various initial concentrations. Batch experiment results with different initial concentrations of nutrient substances demonstrated that the biotransformation of S-(+)-METH occurred simultaneously with the biodegradation of COD and NH4+-N, proving its cometabolism nature. Enzymes released under microbial starvation stress likely stimulated R-(-)-METH biotransformation. Compared with the biotransformation rate of METH under the anaerobic condition, the presence of dissolved oxygen led to a higher biotransformation rate of METH under the aerobic condition.

Biotransformation of 2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ) can contribute to high levels of 2,4,6-tribromophenol (2,4,6-TBP) in humans

2,4,6-Tribromophenol (2,4,6-TBP) is a brominated flame retardant that accumulates in human tissues and is a potential toxicant. Previous studies found 2,4,6-TBP levels in human tissues were significantly higher than those of brominated flame retardants measured in the same samples. In contrast, the levels of 2,4,6-TBP in the environment and foodstuff are not elevated, suggesting a low potential for direct intake through environmental exposure or diet. Here, we hypothesized that high levels of 2,4,6-TBP in human tissues are partially from the indirect exposure sources, such as biotransformation of highly brominated substances. We conducted in vitro assays utilizing human and rat liver microsomes to compare the biotransformation rates of four highly brominated flame retardants, which could potentially transform to 2,4,6-TBP, including decabromodiphenyl ethane (DBDPE), 2,4,6-tris-(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), and tetrabromobisphenol A (TBBPA). Our results show that TTBP-TAZ rapidly metabolizes in both human and rat liver microsomes with a half-life of 1.1 and 2.2 h, respectively, suggesting that TTBP-TAZ is a potential precursor of 2,4,6-TBP. In contrast, 2,4,6-TBP was not formed as a result of biotransformation of TBBPA, BTBPE, and DBDPE in both human and rat liver microsomes. We applied suspect and target screening to explore the metabolic pathways of TTBP-TAZ and identified 2,4,6-TBP as a major metabolite of TTBP-TAZ accounting for 87% of all formed metabolites. These in vitro results were further tested by an in vivo experiment in which 2,4,6-TBP was detected in the rat blood and liver at concentrations of 270 ± 110 and 50 ± 14 μg/g lipid weight, respectively, after being exposed to 250 mg/kg body weight/day of TTBP-TAZ for a week. The hepatic mRNA expression demonstrated that TTBP-TAZ significantly activates the aryl hydrocarbon receptor (AhR) and promotes fatty degeneration (18 and 28-fold change compared to control, respectively) in rats.

Geochemical fluxes in sandy beach aquifers: Modulation due to major physical stressors, geologic heterogeneity, and nearshore morphology

Coastal beach aquifers are biogeochemically active systems that mediate chemical and material fluxes across the land-sea interface. This paper provides a review of major physical stressors and geologic features that influence flow and solute fate and transport in coastal beach aquifers. We outline current understanding of the interactions between these factors and their associated impacts on water and geochemical fluxes within and across these aquifers. The physical processes that control flow, transport, and the formation and distribution of reactive zones in beach aquifers (e.g., tides, waves, density gradients, precipitation, episodic ocean events, and evaporation) operate across overlapping temporal and spatial scales, and present challenges for measuring and modeling physical flow and biogeochemical processes in coastal groundwater systems. Geologic heterogeneity introduces further complexity by modifying flowpaths, mixing patterns, and rates of biotransformation . Interactions between these physical stressors and geological controls are likely to evolve with changes in sea level, climate variability , human settlement, coastal erosion , and other natural and anthropogenic stresses, providing avenues for scientific exploration into the future role of beach aquifers as chemical mediators between the land and ocean.

Using TKTD Models in Combination withIn VivoEnzyme Inhibition Assays to Investigate the Mechanisms behind Synergistic Interactions across Two Species

The aim of this study is to compare the azole synergy across an insect, Chironomus riparius, and a crustacean species, Daphnia magna. We use a combination of in vivo measurements of cytochrome P450 monooxygenase (CYP) biotransformation potential and toxicokinetic (TK) and toxicodynamic (TD) modeling to understand the mechanism behind the synergy of two azole fungicides: the imidazole prochloraz and the triazole propiconazole on the pyrethroid insecticide α-cypermethrin. For both species, the synergistic effect of prochloraz was well-described by its effect on in vivo CYP activity, which corresponded to the biotransformation rate of the TK model parameterized on the survival data of the mixture experiment. For propiconazole, however, there were 100-fold and 50-fold differences between the 50% effect concentration of in vivo CYP activity and the modeled biotransformation rate for C. riparius and D. magna, respectively. Propiconazole, therefore, seems to induce synergy through a mechanism that cannot be quantified solely by the CYP activity assay used in this study in either of the two species. We discuss the differences between prochloraz and propiconazole as synergists across the two species in the light of the type and time dynamics of affected biotransformation processes.

Glucosylation of (±)-Menthol by Uridine-Diphosphate-Sugar Dependent Glucosyltransferases from Plants.

Menthol is a cyclic monoterpene alcohol of the essential oils of plants of the genus Mentha, which is in demand by various industries due to its diverse sensorial and physiological properties. However, its poor water solubility and its toxic effect limit possible applications. Glycosylation offers a solution as the binding of a sugar residue to small molecules increases their water solubility and stability, renders aroma components odorless and modifies bioactivity. In order to identify plant enzymes that catalyze this reaction, a glycosyltransferase library containing 57 uridine diphosphate sugar-dependent enzymes (UGTs) was screened with (±)-menthol. The identity of the products was confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy. Five enzymes were able to form (±)-menthyl-β-d-glucopyranoside in whole-cell biotransformations: UGT93Y1, UGT93Y2, UGT85K11, UGT72B27 and UGT73B24. In vitro enzyme activity assays revealed highest catalytic activity for UGT93Y1 (7.6 nkat/mg) from Camellia sinensis towards menthol and its isomeric forms. Although UGT93Y2 shares 70% sequence identity with UGT93Y1, it was less efficient. Of the five enzymes, UGT93Y1 stood out because of its high in vivo and in vitro biotransformation rate. The identification of novel menthol glycosyltransferases from the tea plant opens new perspectives for the biotechnological production of menthyl glucoside.

CYP3A deficiency alters bile acid homeostasis and leads to changes in hepatic susceptibility in rats

Cytochrome P450 3A (CYP3A) as an important enzyme metabolizes many drugs and a variety of endogenous substances. Bile acids (BA) regulate physiological function by activating BA receptors. In this study, CYP3A1/2 gene knockout (KO) and wild-type (WT) rats were used to investigate the regulatory effects of CYP3A on BA homeostasis and liver function. Compared with WT rats, BA concentrations in serum, liver and small intestine of CYP3A1/2 KO rats increased significantly, which was due to the decrease of catabolism and the increase of synthesis. In particular, the composition of serum BA (overall hydrophobicity) presented an age- and CYP3A-dependent manner. With the aging of WT rats, the serum BA became more hydrophobic, while this trend was delayed in CYP3A1/2 KO rats. Moreover, the level of serum total cholesterol, the precursor of BA synthesis, decreased by about 20% in CYP3A1/2 KO rats, which is due to the low synthesis but high biotransformation rate. The increase of BA pool further led to the change of transcription level of BA receptor in liver (pregnane X receptor) and small intestine (Takeda G-protein receptor 5), and affected the function and morphology of CYP3A1/2 KO rat liver. In conclusion, CYP3A is a key regulator of BA homeostasis in rats, especially in regulating BA pool size, composition and balance of anabolism, and prevents susceptibility to hepatotoxicity under BA overload.

Bacterial Outer Membrane Vesicles as Nano‐Scale Bioreactors: A Fatty Acid Conversion Case Study

AbstractBacterial outer membrane vesicles (OMVs) are small unilamellar proteoliposomes, involved in various functions including cell‐to‐cell signalling and protein excretion. We have engineered the OMVs of Escherichia coli to nano‐scaled bioreactors for the biotransformation of fatty acids by targeting a fatty acid double bond hydratase of Stentrophomonas maltophilia (SmOhyA) and/or a photoactivated fatty acid decarboxylase from Chlorella variabilis NC64 A (CvFAP) into OMVs. Engineered OMVs containing both SmOhyA and CvFAP were able to catalyse the transformation of oleic acid ((Z)‐octadec‐9‐enoic acid) into 9‐hydroxyheptadecane via (R)‐10‐hydroxyoctadecanoic acid. The specific biotransformation rates of oleic acid reached 8.0×10−12 μmol/min per OMV.

Do initial concentration and activated sludge seasonality affect pharmaceutical biotransformation rate constants?

Pharmaceuticals find their way to the aquatic environment via wastewater treatment plants (WWTPs). Biotransformation plays an important role in mitigating environmental risks; however, a mechanistic understanding of involved processes is limited. The aim of this study was to evaluate potential relationships between first-order biotransformation rate constants (kb) of nine pharmaceuticals and initial concentration of the selected compounds, and sampling season of the used activated sludge inocula. Four-day bottle experiments were performed with activated sludge from WWTP Groesbeek (The Netherlands) of two different seasons, summer and winter, spiked with two environmentally relevant concentrations (3 and 30 nM) of pharmaceuticals. Concentrations of the compounds were measured by LC–MS/MS, microbial community composition was assessed by 16S rRNA gene amplicon sequencing, and kb values were calculated. The biodegradable pharmaceuticals were acetaminophen, metformin, metoprolol, terbutaline, and phenazone (ranked from high to low biotransformation rates). Carbamazepine, diatrizoic acid, diclofenac, and fluoxetine were not converted. Summer and winter inocula did not show significant differences in microbial community composition, but resulted in a slightly different kb for some pharmaceuticals. Likely microbial activity was responsible instead of community composition. In the same inoculum, different kb values were measured, depending on initial concentration. In general, biodegradable compounds had a higher kb when the initial concentration was higher. This demonstrates that Michealis-Menten kinetic theory has shortcomings for some pharmaceuticals at low, environmentally relevant concentrations and that the pharmaceutical concentration should be taken into account when measuring the kb in order to reliably predict the fate of pharmaceuticals in the WWTP.Key points• Biotransformation and sorption of pharmaceuticals were assessed in activated sludge.• Higher initial concentrations resulted in higher biotransformation rate constants for biodegradable pharmaceuticals.• Summer and winter inocula produced slightly different biotransformation rate constants although microbial community composition did not significantly change.Graphical abstract

Micropollutant transformation and taxonomic composition in hybrid MBBR – A comparison of carrier-attached biofilm and suspended sludge

The suspended sludge and carrier-attached biofilms of three different hybrid moving bed biofilm reactor (MBBR) systems were investigated with respect to their transformation potential for a broad range of micropollutants (MPs) as well as their microbial community composition. For this purpose, laboratory-scale batch experiments were conducted with the separated suspended sludge and the carrier-attached biofilm of every system in triplicate. For all batches the removal of 31 MPs as well as the composition of the microbial community were analyzed. The carrier-attached biofilms from two hybrid MBBR systems showed a significant higher overall transformation potential in comparison to the respective suspended sludge. Especially for the MPs trimethoprim, diclofenac, mecoprop, climbazole and the human metabolite 10,11-dihydro-10-hydroxycarbamazepine consistently higher pseudo-first-order transformation rates could be observed in all three systems. The analysis of the taxonomic composition revealed taxa showing higher relative abundances in the carrier-attached biofilms (e. g. Nitrospirae and Chloroflexi) and in the suspended biomasses (e. g. Bacteroidetes and Betaproteobacteria). Correlations of the biodiversity indices and the MP biotransformation rates resulted in significant positive associations for 11 compounds in suspended sludge, but mostly negative associations for the carrier-attached biofilms. The distinct differences in MP removal between suspended sludge and carrier-attached biofilm of the three different MBBR systems were also reflected by a statistically significant link between the occurrence of specific bacterial taxa (Acidibacter, Nitrospira and Rhizomicrobium) and MP transformation rates of certain MPs. Even though the identified correlations might not necessarily be of causal nature, some of the identified taxa might serve as suitable indicators for the transformation potential of suspended sludge or carrier-attached biofilms.

Personalized approach to the administration of haloperidol in patients with acute alcoholic hallucinatie (literature review)

To date, it is known that haloperidol is used to treat productive psychopathological symptoms in acute alcoholic hallucinosis, but its use is associated with a high risk of developing undesirable drug reactions (NLR). A number of isoenzymes of the cytochrome P-450 family take part in the metabolism of haloperidol. The biotransformation of haloperidol occurs with the participation of the CYP2D6 isoenzyme encoded by the gene of the same name. The CYP2D6 gene is highly polymorphic, and this polymorphism can lead to a change in the activity of the encoded isoenzyme. Changes in the rate of biotransformation of haloperidol may affect the profile of its effectiveness and safety. This review is aimed at analyzing the information accumulated in the literature on the role of genetic factors in the formation of an individual response to haloperidol therapy in patients with acute alcoholic hallucinosis.

DEUTERIUM AS A TOOL FOR CHANGING THE PROPERTIES OF PHARMACEUTICAL SUBSTANCES (REVIEW)

The review is devoted to the influence of the hydrogen isotope–deuterium on biological models of organisms and the biological activity of pharmaceutical substances.
 The positions of the influence of deuterium on the properties of active pharmaceutical ingredients and excipients are examined from different perspectives. The first position reflects an increase in the kinetic isotope effect (KIE) in processes involving known pharmaceutical substances in aqueous solutions with a deuterium/protium ratio (D/H) below natural. For the first time, the dose-response diagram shows the identity of deuterium with essential trace elements, when a deficiency and excess of an element reduces the organism's vitality. Improved kinetic characteristics are demonstrated for the molecular and organism levels of different hierarchical gradations. In particular, they consist in the possibility of increasing the dissolution rate of substances by influencing the carbohydrate mutarotation processes and the optical activity of chiral substances, increased accumulation of essential elements in medicinal plants and other processes associated with a possible change in metabolic pathways in the cell and the organism as a whole.
 The second considered position of the influence of deuterium is associated with the use of deuterated substances–new compounds or obtained by substitution of protium in known protium analogues. The KIE is presented, which is expressed in a decrease in the biotransformation rate as a result of deuteration, it allows predicting a rapid development of the new direction in the development of drugs. Having an identical therapeutic effect, deuterated analogs provide improved pharmacokinetic characteristics, such as reduced toxicity, blocked epimerization of optically active substances, and a change in the mechanisms of biotransformation. The obtained results make it possible to predict the mechanisms of the effect of deuterium on the biochemical transformations of pharmaceutical substances in the organism.

Temperature, phytoplankton density and bacteria diversity drive the biotransformation of micropollutants in a lake ecosystem

For most micropollutants (MPs) present in surface waters, such as pesticides and pharmaceuticals, the contribution of biotransformation to their overall removal from lake ecosystems is largely unknown. This study aims at empirically determining the biotransformation rate constants for 35 MPs at different periods of the year and depths of a meso-eutrophic lake. We then tested statistically the association of environmental parameters and microbial community composition with the biotransformation rate constants obtained. Biotransformation was observed for 14 out of 35 studied MPs for at least one sampling time. Large variations in biotransformation rate constants were observed over the seasons and between compounds. Overall, the transformation of MPs was mostly influenced by the lake's temperature, phytoplankton density and bacterial diversity. However, some individual MPs were not following the general trend or association with microorganism biomass. The antidepressant mianserin, for instance, was transformed in all experiments and depths, but did not show any relationship with measured environmental parameters, suggesting the importance of specific microorganisms in its transformation. The results presented here contribute to our understanding of the fate of MPs in surface waters and thus support improved risk assessment of contaminants in the environment.

Prediction of an Organic Compound’s Biotransformation Time: A Study Using Avermectins

The current spread of the SARS-CoV-2 coronavirus is a challenge for the entire world. Ivermectin is a promising agent, which could be used to combat the SARS-CoV-2 coronavirus. It represents a complex of semisynthetic derivatives of natural avermectins that have been taken advantage of for a long time in medicine and agriculture as antiparasitic drugs. However, the experimental ecotoxicology assessment data for individual avermectins are still scarce. In relation to this, the aim of this study is to develop a mathematical model that would allow reliably predicting the biotransformation ability of natural and semisynthetic avermectins and identifying the structural fragments of avermectin molecules that have the largest impact on this biological activity. The base for the model construction was a structurally heterogeneous set including organic compounds with experimentally determined biotransformation half-life periods (KmHL). Using the OCHEM web platform (https://ochem.eu) with the implemented PyDescriptor plugin for the descriptor calculation and Random Forest and Transformer-CNN algorithms, a satisfactory (R_{{{text{test}}}}^{2} = 0.81) Quantitative Relationship Structure—Activity (QSAR) model was developed. The subsequent calculations have shown that natural avermectins undergo on average faster biotransformation in fish than the semisynthetic ones. In addition, structural fragments that increase and decrease the biotransformation rate are identified.

Invited Perspective: PFAS Bioconcentration and Biotransformation in Early Life Stage Zebrafish and Its Implications for Human Health Protection.

Invited Perspective: PFAS Bioconcentration and Biotransformation in Early Life Stage Zebrafish and Its Implications for Human Health Protection.

Comparison of the accelerating effect of graphene oxide and graphene on anaerobic transformation of bisphenol F by Pseudomonas sp. LS

ABSTRACT It was found that bisphenol F (BPF) could be anaerobically transformed to 4,4-dihydroxybenzophenone using nitrate as an electron acceptor by Pseudomonas sp. LS. However, BPF removal was a slow process under anaerobic conditions. In the present study, effects of graphene oxide (GO) and graphene on the anaerobic transformation of BPF were studied in detail. Results showed that GO (2-10 mg/L) and graphene (2-20 mg/L) could increase anaerobic biotransformation rate of BPF. For GO-mediated system, GO was partially reduced, and then the reduced GO (rGO) as an electron mediator increased biotransformation rate of BPF. Further analysis showed that the promoting effect of 10 mg/L GO was over 1.5-fold higher compared with that of 10 mg/L graphene. BPF could be transformed using GO as an electron acceptor. GO and graphene were also used as nutrient-scaffolds to promote cell growth via adsorbing proteins. Moreover, GO was a better cell growth promoter than graphene. These studies indicated that GO played more roles and exhibited better accelerating effect on anaerobic removal of BPF compared with graphene.

Cardiopulmonary values and organ blood flows before and during heat stress: data in nine subjects at rest in the upright position.

Physiological changes associated with thermoregulation can influence the kinetics of chemicals in the human body such as alveolar ventilation (VA) and redistribution of blood flow to organs. In this study, the influence of heat stress on various physiological parameters was evaluated in nine male volunteers during sessions of exposure to wet-bulb globe temperatures (WBGT) of 21, 25, and 30°C for 4 h. Skin and core temperatures and more than 20 cardiopulmonary parameters were measured. Liver, kidneys, brain, skin, and muscles blood flows were also determined based on published measurements. Results show that most subjects (eight out of nine) have been affected by the inhalation of hot and dry air at the WBGT of 30°C. High respiratory rates, superficial tidal volumes, and low VA values were notably observed. The skin blood flow increased by 2.16-fold, whereas the renal blood flow and liver blood flow decreased by about by 11% and 18%, respectively. A complete set of key cardiopulmonary parameters in healthy male adults before and during heat stress was generated for use in physiologically based pharmacokinetic modeling. A toxicokinetic studies are ongoing to evaluate the impact of heat stress on the absorption, biotransformation and excretion rates of volatile xenobiotics.

Elemental sulphur production from thiosulphate under haloalkaline conditions in a Thioalkalivibrio versutus amended fluidized bed bioreactor

Concentrated sulphurous and saline streams, produced for example by pulp and paper and petrochemical industries, pose challenges for both environmental and processes management. In this study, the potential of biological recovery of S0 from haloalkaline thiosulphate solution in a Thioalkalivibrio versutus amended continuous-flow fluidized bed bioreactor (FBBR) was investigated using different (12−5 h) hydraulic retention times (HRT) as well as physico-chemical means to separate the S0 produced. S2O32− was biotransformed to SO42− and S0 with the highest biotransformation efficiency of 99.9 %. At 7 h HRT, the capacity of the FBBR was reached, seen as incomplete thiosulphate conversion. S0 production rate increased up to 6.3 ± 0.6 g S/l/d at HRT 7 h, whilst the average S0 yield was 27 ± 2 %. The presence of biologically produced S0 was visual and identified by scanning electron microscopy. Separation of S0 from the effluent by centrifugation at 3417 relative centrifugal force (rcf) resulted in 93 % separation, while among the four tested coagulants, FeCl2 at 0.5 g/l resulted in 40 % separation. Also, FeCl2 enhanced thiosulphate biotransformation rates. In summary, continuous biological S0 production followed by separation by centrifugation indicates potential for sulphur recovery from alkaline and saline industrial streams.

QSARINS-Chem standalone version: A new platform-independent software to profile chemicals forphysico-chemical properties, fate, and toxicity.

The new software QSARINS‐Chem standalone version is a multiplatform tool, freely downloadable, for the in silico profiling of multiple properties and activities of organic chemicals. This software, which is based on the concept of the QSARINS‐chem module embedded in the QSARINS software, has been fully redesigned and redeveloped in the Java™ language. In addition to a selection of models included in the old module, the new software predicts biotransformation rates and aquatic toxicities of pharmaceuticals and personal care products in multiple organisms, and offers a suite of tools for the analysis of predictions. Furthermore, a comprehensive and transparent database of molecular structures is provided. The new QSARINS‐Chem standalone version is an informative and solid tool, which is useful to support the assessment of the potential hazard and risks related to organic chemicals and is dedicated to users which are interested in the application of QSARs to generate reliable predictions.

Evaluation and comparison of in vitro intrinsic clearance rates measured using cryopreserved hepatocytes from humans, rats, and rainbow trout

In vitro and in silico methods that can reduce the need for animal testing are being used with increasing frequency to assess chemical risks to human health and the environment. The rate of hepatic biotransformation is an important species-specific parameter for determining bioaccumulation potential and extrapolating in vitro bioactivity to in vivo effects. One approach to estimating hepatic biotransformation is to employ in vitro systems derived from liver tissue to measure chemical (substrate) depletion over time which can then be translated to a rate of intrinsic clearance (CLint). In the present study, cryopreserved hepatocytes from humans, rats, and rainbow trout were used to measure CLint values for 54 industrial and pesticidal chemicals at starting test concentrations of 0.1 and 1 μM. A data evaluation framework that emphasizes the behavior of Heat-Treated Controls (HTC) was developed to identify datasets suitable for rate reporting. Measured or estimated (“greater than” or “less than”) CLint values were determined for 124 of 226 (55 %) species-chemical-substrate concentration datasets with acceptable analytical chemistry. A large percentage of tested chemicals exhibited low HTC recovery values, indicating a substantial abiotic loss of test chemical over time. An evaluation of KOW values for individual chemicals suggested that in vitro test performance declined with increasing chemical hydrophobicity, although differences in testing devices for mammals and fish also likely played a role. The current findings emphasize the value of negative controls as part of a rigorous approach to data quality assessment for in vitro substrate depletion studies. Changes in current testing protocols can be expected to result in the collection of higher quality data. However, poorly soluble chemicals are likely to remain a challenge for CLint determination.

Development and intercomparison of single and multicompartment physiologically-based toxicokinetic models: Implications for model selection and tiered modeling frameworks

This study describes the development and intercomparison of generic physiologically-based toxicokinetic (PBTK) models for humans comprised of internally consistent one-compartment (1Co-) and multi-compartment (MCo-) implementations (G-PBTK). The G-PBTK models were parameterized for an adult male (70 kg) using common physiological parameters and in vitro biotransformation rate estimates and subsequently evaluated using independent concentration versus time data (n = 6) and total elimination half-lives (n = 15) for diverse organic chemicals. The model performance is acceptable considering the inherent uncertainty in the biotransformation rate data and the absence of model calibration. The G-PBTK model was then applied using hypothetical neutral organics, acidic ionizable organics and basic ionizable organics (IOCs) to identify combinations of partitioning properties and biotransformation rates leading to substantial discrepancies between 1Co- and MCo-PBTK calculations for whole body concentrations and half-lives. The 1Co- and MCo-PBTK model calculations for key toxicokinetic parameters are broadly consistent unless biotransformation is rapid (e.g., half-life less than five days). When half-lives are relatively short, discrepancies are greatest for the neutral organics and least for the acidic IOCs which follows from the estimated volumes of distribution (e.g., VDSS = 9.6–15.4 L/kg vs 0.3–1.6 L/kg for the neutral and acidic compounds respectively) and the related approach to internal chemical equilibrium. The model intercomparisons demonstrate that 1Co-PBTK models can be applied with confidence to many exposure scenarios, particularly those focused on chronic or repeat exposures and for prioritization and screening-level decision contexts. However, MCo-PBTK models may be necessary in certain contexts, particularly for intermittent, short-term and highly variable exposures. A key recommendation to guide model selection and the development of tiered PBTK modeling frameworks that emerges from this study is the need to harmonize models with respect to parameterization and process descriptions to the greatest extent possible when proceeding from the application of simpler to more complex modeling tools as part of chemical assessment activities.