Effects of PFAS on human liver transporters: implications for health outcomes.

Per- and polyfluoroalkyl substances (PFAS) have become internationally recognized over the past three decades as persistent organic pollutants used in the production of various consumer and industrial goods. Research efforts continue to gauge the risk that historically used, and newly produced, PFAS may cause to human health. Numerous studies report toxic effects of PFAS on the human liver as well as increased serum cholesterol levels in adults. A major concern with PFAS, also dubbed "forever chemicals", is that they accumulate in liver and kidney and persist in serum. The mechanisms responsible for their disposition and excretion in humans are poorly understood. A better understanding of the interaction of PFAS with liver transporters, as it pertains to the disposition of PFAS and other xenobiotics, could provide mechanistic insight into human health effects and guide efforts toward risk assessment of compounds in development. This review summarizes the current state of the literature on the emerging relationships (e.g., substrates, inhibitors, modulators of gene expression) between PFAS and specific hepatic transporters. The adaptive and toxicological responses of hepatocytes to PFAS that reveal linkages to pathologies and epidemiological findings are highlighted. The evidence suggests that our understanding of the molecular landscape of PFAS must improve to determine their impact on the expression and function of hepatocyte transporters that play a key role in PFAS or other xenobiotic disposition. From here, we can assess what role these changes may have in documented human health outcomes.

Role of albumin in the metabolism and excretion of ochratoxin A.

Ochratoxin A (OTA) is known to be strongly bound to serum albumin, but it remains unknown how albumin affects its metabolism and kinetics. To close this gap, we used a mouse model, where heterozygous albumin deletion reduces serum albumin to concentrations similar to hypoalbuminemic patients and completely eliminates albumin by a homozygous knockout. OTA and its potential metabolites (OTα, 4-OH-OTA, 7'-OH-OTA, OTHQ, OP-OTA, OTB-GSH, OTB-NAC, OTB) were time-dependently analyzed in plasma, bile, and urine by LC-MS/MS and were compared to previously published hepatotoxicity and nephrotoxicity data. Homozygous albumin deletion strongly accelerated plasma clearance as well as biliary and urinary excretion of the parent compound and its hydroxylation products. Decreasing albumin in mice by the heterozygous and even more by the homozygous knockout leads to an increase in the parent compound in urine which corresponded to increased nephrotoxicity. The role of albumin in OTA-induced hepatotoxicity is more complex, since heterozygous but not homozygous nor wild-type mice showed a strong biliary increase in the toxic open lactone OP-OTA. Correspondingly, OTA-induced hepatotoxicity was higher in heterozygous than in wild-type and homozygous animals. We present evidence that albumin-mediated retention of OTA in hepatocytes is required for formation of the toxic OP-OTA, while complete albumin elimination leads to rapid biliary clearance of OTA from hepatocytes with less formation of OP-OTA. In conclusion, albumin has a strong influence on metabolism and toxicity of OTA. In hypoalbuminemia, the parent OTA is associated with increased nephrotoxicity and the open lactone with increased hepatotoxicity.

Potential impact of underlying diseases influencing ADME in nonclinical safety assessment.

Nonclinical studies involve in vitro, in silico, and in vivo experiments to assess the toxicokinetics, toxicology, and safety pharmacology of drugs according to regulatory requirements by a national or international authority. In this review, we summarize the potential effects of various underlying diseases governing the absorption, distribution, metabolism, and excretion (ADME) of drugs to consider the use of animal models of diseases in nonclinical trials. Obesity models showed alterations in hepatic metabolizing enzymes, transporters, and renal pathophysiology, which increase the risk of drug-induced toxicity. Diabetes models displayed changes in hepatic metabolizing enzymes, transporters, and glomerular filtration rates (GFR), leading to variability in drug responses and susceptibility to toxicity. Animal models of advanced age exhibited impairment of drug metabolism and kidney function, thereby reducing the drug-metabolizing capacity and clearance. Along with changes in hepatic metabolic enzymes, animal models of metabolic syndrome-related hypertension showed renal dysfunction, resulting in a reduced GFR and urinary excretion of drugs. Taken together, underlying diseases can induce dysfunction of organs involved in the ADME of drugs, ultimately affecting toxicity. Therefore, the use of animal models of representative underlying diseases in nonclinical toxicity studies can be considered to improve the predictability of drug side effects before clinical trials.

Inhibition of human drug transporter activities by succinate dehydrogenase inhibitors.

Succinate dehydrogenase inhibitors (SDHIs) are widely-used fungicides, to which humans are exposed and for which putative health risks are of concern. In order to identify human molecular targets for these environmental chemicals, the interactions of 15 SDHIs with activities of main human drug transporters implicated in pharmacokinetics were investigated in vitro. 5/15 SDHIs, i.e., benzovindiflupyr, bixafen, fluxapyroxad, pydiflumetofen and sedaxane, were found to strongly reduce activity of the renal organic anion transporter (OAT) 3, in a concentration-dependent manner (with IC50 values in the 1.0-3.9 µM range), without however being substrates for OAT3. Moreover, these 5/15 SDHIs decreased the membrane transport of estrone-3 sulfate, an endogenous substrate for OAT3, and sedaxane was predicted to inhibit in vivo OAT3 activity in response to exposure to the acceptable daily intake (ADI) dose. In addition, pydiflumetofen strongly inhibited the renal organic cation transporter (OCT) 2 (IC50 = 2.0 µM) and benzovindiflupyr the efflux pump breast cancer resistance protein (BCRP) (IC50 = 3.9 µM). Other human transporters, including organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 as well as multidrug and toxin extrusion protein (MATE) 1 and MATE2-K were moderately or weakly inhibited by SDHIs, whereas P-glycoprotein, multidrug resistance-associated protein (MRP), OCT1 and OAT1 activities were not or only marginally impacted. Then, some human drug transporters, especially OAT3, constitute molecular targets for SDHIs. This could have toxic consequences, notably with respect to levels of endogenous compounds and metabolites substrates for the considered transporters or to potential SDHI-drug interactions. This could therefore contribute to putative health risk of these fungicides.

Exploring the potential and challenges of developing physiologically-based toxicokinetic models to support human health risk assessment of microplastic and nanoplastic particles.

Microplastics (MPs) and nanoplastics (NPs) pollution has emerged as a significant and widespread environmental issue. Humans are inevitably exposed to MPs and NPs via ingestion, inhalation, and dermal contacts from various sources. However, mechanistic knowledge of their distribution, interaction, and potency in the body is still lacking. To address this knowledge gap, we have undertaken the task of elucidating the toxicokinetic (TK) behaviors of MPs and NPs, aiming to provide mechanistic information for constructing a conceptual physiologically based toxicokinetic (PBTK) model to support in silico modeling approaches. Our effort involved a thorough examination of the existing literature and data collation on the presence of MPs in the human body and in vitro/ex vivo/in vivo biodistribution across various cells and tissues. By comprehending the absorption, distribution, metabolism, and excretion mechanisms of MPs and NPs in relation to their physicochemical attributes, we established a foundational understanding of the link between external exposure and internal tissue dosimetry. We observed that particle size and surface chemistry have been thoroughly explored in previous experimental studies. However, certain attributes, such as polymer type, shape, and biofilm/biocorona, warrant attention and further examination. We discussed the fundamental disparities in TK properties of MPs/NPs from those of engineered nanoparticles. We proposed a preliminary PBTK framework with several possible modeling approaches and discussed existing challenges for further investigation. Overall, this article provides a comprehensive compilation of existing TK data of MPs/NPs, a critical overview of TK processes and mechanisms, and proposes potential PBTK modeling approaches, particularly regarding their applicability to the human system, and outlines future perspectives for developing PBTK models and their integration into human health risk assessment of MPs and NPs.

Repeated-dose toxicity and toxicokinetic study of isobutylparaben in rats subcutaneously treated for 13 weeks.

Parabens have historically served as antimicrobial preservatives in a range of consumables such as food, beverages, medications, and personal care products due to their broad-spectrum antibacterial and antifungal properties. Traditionally, these compounds were believed to exhibit low toxicity, causing minimal irritation, and possessing limited sensitization potential. However, recent evidence suggests that parabens might function as endocrine-disrupting chemicals (EDCs). Consequently, extensive research is underway to elucidate potential human health implications arising from exposure to these substances. Among these parabens, particular concerns have been raised regarding the potential adverse effects of iso-butylparaben (IBP). Studies have specifically highlighted its potential for inducing hormonal disruption, significant ocular damage, and allergic skin reactions. This study aimed to evaluate the prolonged systemic toxicity, semen quality, and estrus cycle in relation to endocrine disruption endpoints, alongside assessing the toxicokinetic behavior of IBP in Sprague-Dawley rats following a 13-week repeated subcutaneous administration. The rats were administered either the vehicle (4% Tween 80) or IBP at dosage levels of 2, 10, and 50 mg/kg/day for 13 weeks. Blood collection for toxicokinetic study was conducted on three specified days: day 1 (1st), day 30 (2nd), and day 91 (3rd). Systemic toxicity assessment and potential endocrine effects were based on various parameters including mortality rates, clinical signs, body weights, food and water consumption, ophthalmological findings, urinalysis, hematological and clinical biochemistry tests, organ weights, necropsy and histopathological findings, estrus cycle regularity, semen quality, and toxicokinetic behavior. The findings revealed that IBP induced local irritation at the injection site in males at doses ≥ 10 mg/kg/day and in females at 50 mg/kg/day; however, systemic toxicity was not observed. Consequently, the no-observed-adverse-effect level (NOAEL) for IBP was determined to be 50 mg/kg/day in rats of both sexes, indicating no impact on the endocrine system. The toxicokinetics of IBP exhibited dose-dependent systemic exposure, reaching a maximum dose of 50 mg/kg/day, and repeated administration over 13 weeks showed no signs of accumulation.

Biotransformation and toxicokinetics of 2-phenoxyethanol after oral exposure in humans: a volunteer study.

2-Phenoxyethanol (PhE) is an aromatic glycol ether and is used in a variety of functions and applications, e.g., as preservative in pharmaceuticals, cosmetic and personal care products, as biocide in disinfectants (e.g. human hygiene), or as a solvent in formulations (e.g. coatings, functional fluids). Despite its widespread use, little is yet known on its biotransformation and toxicokinetics in humans. Therefore, a pilot study was conducted with oral administration of PhE (5 mg/kg body weight) to five volunteers. Blood and urine samples were collected and analyzed for PhE and three of its presumed metabolites up to 48 h post-exposure. Additionally, one volunteer was dermally exposed to PhE and monitored until 72 h post-exposure. PhE was rapidly resorbed following both oral and dermal application with tmax-levels in blood of about 1 h and 3 h, respectively. Metabolism of PhE was observed to be rather extensive with phenoxyacetic acid (PhAA) and 4-hydroxyphenoxyacetic acid (4-OH-PhAA) as the main metabolites found in blood and urine following oral and dermal exposure. PhE was excreted rapidly and efficiently via urine mostly in metabolized form: following oral exposure, on average 77% and 12% of the applied dose was excreted within 48 h as PhAA and 4-OH-PhAA, respectively. A similar metabolism pattern was observed following the single dermal exposure experiment. The obtained data on biotransformation and toxicokinetics of PhE in humans provide valuable information on this important chemical and will be highly useful for pharmacokinetic modelling and evaluation of human PhE exposure.

Trophic Transfer and Toxic Potency of Rare Earth Elements along a Terrestrial Plant-Herbivore Food Chain.

Extensive rare earth element (REE) mining activities have caused REE contamination of ambient agricultural soils, posing threats to associated food webs. Here, a simulated lettuce-snail food chain was conducted to evaluate the trophic transfer characteristics and the consequent effects of REEs on consumers. After 50-day exposure to soil, lettuce roots dose-dependently accumulated 9.4-76 mg kg-1 REEs and translocated 3.7-20 mg kg-1 REEs to shoots. Snails feeding on REE-contaminated shoots accumulated 3.0-6.7 mg kg-1 REEs with trophic transfer factors of 0.20-0.98, indicating trophic dilution in the lettuce-snail system. REE profiles in lettuce and snails indicated light REE (LREE) enrichment only in snails and the varied REE profiles along the food chain. This was corroborated by toxicokinetics. Estimated uptake (Ku) and elimination (Ke) parameters were 0.010-2.9 kgshoot kgsnail-1 day-1 and 0.010-1.8 day-1, respectively, with higher Ku values for LREE and HREE. The relatively high Ke, compared to Ku, indicating a fast REE elimination, supports the trophic dilution. Dietary exposure to REEs dose-dependently affected gut microbiota and metabolites in snails. These effects are mainly related to oxidative damage and energy expenditure, which are further substantiated by targeted analysis. Our study provides essential information about REE bioaccumulation characteristics and its associated risks to terrestrial food chains near REE mining areas.

The amnesic shellfish poisoning toxin, domoic acid: The tattoo of the king scallop Pecten maximus.

Domoic acid (DA) is a potent neurotoxin produced by diatoms of the genus Pseudo-nitzschia and is responsible for Amnesic Shellfish Poisoning (ASP) in humans. Some fishery resources of high commercial value, such as the king scallop Pecten maximus, are frequently exposed to toxic Pseudo-nitzschia blooms and are capable of accumulating high amounts of DA, retaining it for months or even a few years. This poses a serious threat to public health and a continuous economical risk due to fishing closures of this resource in the affected areas. Recently, it was hypothesized that trapping of DA within autophagosomic-vesicles could be one reason explaining the long retention of the remaining toxin in P. maximus digestive gland. To test this idea, we follow the kinetics of the subcellular localization of DA in the digestive glands of P. maximus during (a) the contamination process - with sequential samplings of scallops reared in the field during 234 days and naturally exposed to blooms of DA-producing Pseudo-nitzschia australis, and (b) the decontamination process - where highly contaminated scallops were collected after a natural bloom of toxic P. australis and subjected to DA-depuration in the laboratory for 60 days. In the digestive gland, DA-depuration rate (0.001 day-1) was much slower than contamination kinetics. The subcellular analyses revealed a direct implication of early autophagy in DA sequestration throughout contamination (r = 0.8, P < 0.05), while the presence of DA-labeled residual bodies (late autophagy) appeared to be strongly and significantly related to slow DA-depuration (r = -0.5) resembling an analogous DA-tattooing in the digestive glands of P. maximus. This work provides new evidence about the potential physiological mechanisms involved in the long retention of DA in P. maximus and represents the baseline to explore procedures to accelerate decontamination in this species.

Toxicokinetics of MDMA and Its Metabolite MDA in Rats.

OBJECTIVES: To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA. METHODS: A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis. RESULTS: In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: T=10.362C-1.183, R2=0.974 6; T=7.397 3C-0.694, R2=0.961 5 (T: injection time; C: concentration ratio of MDMA to MDA in plasma). CONCLUSIONS: The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.

Quantitative differentiation of toxicity contributions and predicted global risk of fipronil and its transformation products to aquatic invertebrates.

Biotransformation often alters chemical toxicity, yet its impacts on risk assessment are hardly quantified due to the challenges in acquiring internal exposure-based thresholds for chemicals that are readily metabolizable. Here, we integrated toxic unit and toxicokinetics to quantitatively assess toxicity contributions and potential risk of both parent compound and transformation products (TPs) to aquatic organisms, using fipronil (FIP) as a representative toxicant. In aquatic invertebrates Chironomus dilutus and Hyalella azteca, approximately 90 % of FIP was transformed to fipronil sulfone (SUL). FIP and SUL exhibited similar intrinsic toxicity to these organisms, which was contrary to conventional perception that SUL was more toxic than FIP. However, biotransformation was still important in risk assessment because the TP had 10-fold slower depuration rate than FIP. The amphipod H. azteca was found to be as sensitive to FIPs as the insect C. dilutus, which was previously considered ten times more sensitive based on external thresholds. This discrepancy has led to overlooking the toxicity of FIP to H. azteca in regional risk assessments. Lastly, we predicted the lethal risk of FIPs in global surface water. When using external thresholds for prediction, FIPs in 3.4 % of the water samples were lethally toxic to H. azteca, and the percentage of water samples at risk increased to 14 % when internal thresholds were used and SUF dominated the risk. This study presents an improved method for quantifying aquatic risk of readily metabolized toxicants. Our findings underscore the urgency of considering TPs in water quality assessments, especially for sensitive species that are at risk in the environment.

Photoaged polystyrene nanoplastics exposure results in reproductive toxicity due to oxidative damage in Caenorhabditis elegans.

The increase of plastic production together with the incipient reuse/recycling system has resulted in massive discards into the environment. This has facilitated the formation of micro- and nanoplastics (MNPs) which poses major risk for environmental health. Although some studies have investigated the effects of pristine MNPs on reproductive health, the effects of weathered MNPs have been poorly investigated. Here we show in Caenorhabditis elegans that exposure to photoaged polystyrene nanoplastics (PSNP-UV) results in worse reproductive performance than pristine PSNP (i.e., embryonic/larval lethality plus a decrease in the brood size, accompanied by a high number of unfertilized eggs), besides it affects size and locomotion behavior. Those effects were potentially generated by reactive products formed during UV-irradiation, since we found higher levels of reactive oxygen species and increased expression of GST-4 in worms exposed to PSNP-UV. Those results are supported by physical-chemical characterization analyses which indicate significant formation of oxidative degradation products from PSNP under UV-C irradiation. Our study also demonstrates that PSNP accumulate predominantly in the gastrointestinal tract of C. elegans (with no accumulation in the gonads), being completely eliminated at 96 h post-exposure. We complemented the toxicological analysis of PSNP/PSNP-UV by showing that the activation of the stress response via DAF-16 is dependent of the nanoplastics accumulation. Our data suggest that exposure to the wild PSNP, i.e., polystyrene nanoplastics more similar to those actually found in the environment, results in more important reprotoxic effects. This is associated with the presence of degradation products formed during UV-C irradiation and their interaction with biological targets.

Toxicokinetics of homosalate in humans after dermal application: applicability of oral-route data for exposure assessment by human biomonitoring.

Homosalate (HMS) is a UV filter used in sunscreens and personal care products as a mixture of cis- and trans-isomers. Systemic absorption after sunscreen use has been demonstrated in humans, and concerns have been raised about possible endocrine activity of HMS, making a general population exposure assessment desirable. In a previous study, it was shown that the oral bioavailability of cis-HMS (cHMS) is lower than that of trans-HMS (tHMS) by a factor of 10, calling for a separate evaluation of both isomers in exposure and risk assessment. The aim of the current study is the investigation of HMS toxicokinetics after dermal exposure. Four volunteers applied a commercial sunscreen containing 10% HMS to their whole body under regular-use conditions (18-40 mg HMS (kg bw)-1). Parent HMS isomers and hydroxylated and carboxylic acid metabolites were quantified using authentic standards and isotope dilution analysis. Further metabolites were investigated semi-quantitatively. Elimination was delayed and slower compared to the oral route, and terminal elimination half-times were around 24 h. After dermal exposure, the bioavailability of cHMS was a factor of 2 lower than that of tHMS. However, metabolite ratios in relation to the respective parent isomer were very similar to the oral route, supporting the applicability of the oral-route urinary excretion fractions for dermal-route exposure assessments. Exemplary calculations of intake doses showed margins of safety between 11 and 92 (depending on the approach) after single whole-body sunscreen application. Human biomonitoring can reliably quantify oral and dermal HMS exposures and support the monitoring of exposure reduction measures.

A combined toxicokinetic and metabolic approach to investigate deschloro-N-ethylketamine exposure in a multidrug user.

The use of new psychoactive substances derived from ketamine is rarely reported in France. A chronic GHB, 3-MMC, and methoxetamine consumer presented a loss of consciousness in a chemsex context and was referred to the intensive care unit with a rapid and favorable outcome. To investigate the chemicals responsible for the intoxication, a comprehensive analysis was conducted on the ten plasma samples collected over a 29.5-hour period, urine obtained upon admission, a 2-cm hair strand sample, and a seized crystal. These analyses were performed using liquid chromatography hyphenated to high resolution tandem mass spectrometry operating in targeted and untargeted modes. Additionally, analyses using gas chromatography coupled to mass spectrometry and nuclear magnetic resonance were conducted to probe the composition of the seized crystal. The molecular network-based approach was employed for data processing in non-targeted analyses. It allowed to confirm a multidrug exposure encompassing GHB, methyl-(aminopropyl)benzofuran (MAPB), (aminopropyl)benzofuran (APB), methylmethcathinone, chloromethcathinone, and a new psychoactive substance belonging to the arylcyclohexylamine family namely deschloro-N-ethyl-ketamine (O-PCE). Molecular network analysis facilitated the annotation of 27 O-PCE metabolites, including phase II compounds not previously reported. Plasma kinetics of O-PCE allowed the estimation of the elimination half-life of ∼5 hours. Kinetics of O-PCE metabolites was additionally characterized, possibly useful as surrogate biomarkers of consumption. We also observed marked alterations in lipid metabolism related to poly consumption of drugs. In conclusion, this case report provides a comprehensive analysis of exposure to O-PCE in a multidrug user including kinetic and metabolism data in human.

The Toxicokinetics, Excretion Patterns, and Milk Transmission of Ochratoxin A in Lactating Sows.

Ochratoxin A (OTA), a mycotoxin commonly found in feedstuffs, is known for its detrimental effects on the kidneys and liver, posing significant health risks to animals and humans. This study investigated the toxicokinetics, excretion patterns, and milk transmission of Ochratoxin A (OTA) in lactating sows. The sows were administered a single oral dose of 500 µg/kg BW (body weight), followed by the systematic sampling of plasma, feces, urine, and milk. Plasma samples were collected at 0, 5, 15, and 30 min, and 1, 2, 3, 6, 9, 12, 24, 48, 72, 88, 96, and 120 h post administration. Feces samples were collected at 6 h intervals for the first 12 h, then at 12 h intervals until 120 h, while urine samples were collected at 6 h intervals up to 120 h. Milk samples were collected at 0, 6, 12, 24, 36, 48, 72, 96, and 120 h. The concentration of OTA and its primary metabolite OTα were quantitatively analyzed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results revealed that the peak plasma concentrations of OTA (920.25 ± 88.46 µg/L) were observed at 9 h following administration. The terminal elimination half-life was recorded at 78.47 ± 7.68 h, with a volume of distribution of 0.16 ± 0.003 L/kg. Moreover, this study documented the excretion of OTA and OTα across a span of 120 h, revealing that feces and urine accounted for 18.70 ± 0.04% and 8.40 ± 0.002% of the total intake amounts, respectively (calculated based on substance amounts). Furthermore, this experiment detected OTA residues in the milk of lactating sows, with the milk-to-plasma (M/P) ratio initially increasing from 0.06 to 0.46 within the first 24 h following OTA ingestion. These findings offer an exhaustive temporal analysis of OTA's toxicokinetics in lactating sows, emphasizing its pervasive distribution and elimination through various bodily excreta.

Emerging organic contaminants in drinking water systems: Human intake, emerging health risks, and future research directions.

Few earlier reviews on emerging organic contaminants (EOCs) in drinking water systems (DWS) focused on their detection, behaviour, removal and fate. Reviews on multiple exposure pathways, human intake estimates, and health risks including toxicokinetics, and toxicodynamics of EOCs in DWS are scarce. This review presents recent advances in human intake and health risks of EOCs in DWS. First, an overview of the evidence showing that DWS harbours a wide range of EOCs is presented. Multiple human exposure to EOCs occurs via ingestion of drinking water and beverages, inhalation and dermal pathways are discussed. A potential novel exposure may occur via the intravenous route in dialysis fluids. Analysis of global data on pharmaceutical pollution in rivers showed that the cumulative concentrations (µg L-1) of pharmaceuticals (mean ± standard error of the mean) were statistically more than two times significantly higher (p = 0.011) in South America (11.68 ± 5.29), Asia (9.97 ± 3.33), Africa (9.48 ± 2.81) and East Europe (8.09 ± 4.35) than in high-income regions (2.58 ± 0.48). Maximum cumulative concentrations of pharmaceuticals (µg L-1) decreased in the order; Asia (70.7) had the highest value followed by South America (68.8), Africa (51.3), East Europe (32.0) and high-income regions (17.1) had the least concentration. The corresponding human intake via ingestion of untreated river water was also significantly higher in low- and middle-income regions than in their high-income counterparts. For each region, the daily intake of pharmaceuticals was highest in infants, followed by children and then adults. A critique of the human health hazards, including toxicokinetics and toxicodynamics of EOCs is presented. Emerging health hazards of EOCs in DWS include; (1) long-term latent and intergenerational effects, (2) the interactive health effects of EOC mixtures, (3) the challenges of multifinality and equifinality, and (4) the Developmental Origins of Health and Disease hypothesis. Finally, research needs on human health hazards of EOCs in DWS are presented.

Carboxyhemoglobin half-life toxicokinetic profiles during and after normobaric oxygen therapy: On a swine model.

Investigations on acute carbon monoxide (CO) poisoning struggle to highlight a relevant discriminant criterion related to CO poisoning severity for predicting complications, such as delayed neurological syndromes. In this context, it remains difficult to demonstrate the superiority of one method of oxygen (O2) administration over others or to identify the optimal duration of normobaric 100% oxygen (NBO) treatment. Myoglobin, as hemoglobin, are a potential binding site for CO, which could be a source of extravascular CO storage that impacts the severity of CO poisoning. It is not possible in routine clinical practice to estimate this potential extravascular CO storage. Indirect means of doing so that are available in the first few hours of poisoning could include, for example, the carboxyhemoglobin half-life (COHbt1/2), which seems to be influenced itself by the level and duration of CO exposure affecting this store of CO within the body. However, before the elimination of CO can be assessed, the COHbt1/2 toxicokinetic model must be confirmed: research still debates whether this model mono- or bi-compartmental. The second indirect mean could be the assessment of a potential COHb rebound after COHb has returned to 5% and NBO treatment has stopped. Moreover, a COHb rebound could be considered to justify the duration of NBO treatment. On an experimental swine model exposed to moderate CO poisoning (940 ppm for ±118 min until COHb reached 30%), we first confirm that the COHb half-life follows a bi-compartmental model. Secondly, we observe for the first time a slight COHb rebound when COHb returns to 5% and oxygen therapy is stopped. On the basis of these two toxicokinetic characteristics in favor of extravascular CO storage, we recommend that COHbt1/2 is considered using the bi-compartmental model in future clinical studies that compare treatment effectiveness as a potential severity criterion to homogenize cohorts of the same severity. Moreover, from a general toxicokinetic point of view, we confirm that a treatment lasting less than 6 hours appears to be insufficient for treating moderate CO poisoning.

Identifying and Predicting Delayed Mortality with Toxicokinetic-Toxicodynamic Models.

The prevalence of standardized toxicity testing in ecotoxicology has largely obscured the notion that toxicity is a function of time as well. The necessity of considering time is vividly demonstrated by observations of delayed mortality, that is, deaths continue to occur even when animals are no longer exposed to a toxicant. In this contribution, I explore to what extent toxicokinetic-toxicodynamic (TKTD) models from the framework of the General Unified Threshold model for Survival (GUTS) can capture delayed mortality, and to what extent this phenomenon can be predicted from short-term standard tests. I use a previously published data set for fluoroquinolones in Daphnia magna that shows strongly delayed mortality (using immobilization as a proxy for death). The model analysis shows that the GUTS stochastic death models can capture delayed mortality in the complete data set with a long recovery phase, but that the delayed effects would not have been predicted from a 2-day standard test. The study underlines the limited information content of standard acute test designs. Toxicokinetic-toxicodynamic modeling offers a handle on the time aspects of toxicity but cannot always be relied on to provide accurate extrapolations based on severely limited standard tests. The phenomenon of delayed toxicity requires more structured study to clarify its prevalence and impact; I discuss several avenues for further investigation. Environ Toxicol Chem 2024;43:1030-1035. © 2024 SETAC.

Effect of salinity on the toxicokinetics, oxidative stress, and metallothionein gene expression in Meretrix meretrix exposed to cadmium.

To understand the effect of salinity on the toxicokinetics, oxidative stress, and detoxification of cadmium-exposed Meretrix meretrix, M. meretrix were acclimatized to different salinities (8, 14, 20, 26, and 32 ppt) for 14 d, exposed to 10 µg/L Cd for 7 d, followed by a 28-day depuration period. The internal Cd concentration was determined, and the activities of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione-S-transferase (GST)), and the malondialdehyde (MDA) content were measured. The mRNA expression levels of antioxidant enzyme (Cu/Zn SOD, CAT) and detoxification-related genes metallothionein (MT) were analyzed. The mean concentrations of Cd in M. meretrix tissues were in the order gill > digestive gland > mantle > axe foot. The Cd uptake rate in the four tissues decreased with increasing salinity (range: 14-26 ppt). The Cd elimination half-lives were the highest at 8 ppt and 14 ppt salinity. Cadmium activated the four oxidative stress-related related enzymes in the gills. At the end of accumulation period, Cd exposure at 20 ppt salinity significantly increased the expression of Cu/Zn SOD. CAT expression was significantly inhibited at 20 ppt salinity, but was induced at 32 ppt. MT mRNA expression was only induced under Cd at 20 ppt salinity. At the end of depuration period, Cu/Zn SOD expression was inhibited at salinities of 8, 14, and 26 ppt. The results indicated that SOD, CAT, GST, MDA, Cu/Zn SOD, CAT, and MT were sensitive to cadmium in a water environment, and can be used as indicators of marine heavy metal pollution.

Toxicokinetic analysis of the highly toxic nerve agent VX in commercially available multi-organ-chips - Ways to overcome compound absorption.

Organ-on-a-chip technology is considered a next-generation platform in pharmacology and toxicology. Nevertheless, this novel technology still faces several challenges concerning the respective materials which are used for these microfluidic devices. Currently available organ-chips are most often based on polydimethylsiloxane (PDMS). However, this material has strong limitations regarding compound binding. The current study investigated options to reduce compound absorption of the highly toxic nerve agent VX (1000 µmol/L) in a commercially available organ-chip. In addition, surface effects on degradation products of VX were investigated. The alternative polymer cyclic olefin copolymers (CoC) showed significantly less compound absorption compared to PDMS. Furthermore, a coating of PDMS- and CoC-based chips was investigated. The biocompatible polymer polyethyleneimine (PEI) successfully modified PDMS and CoC surfaces and further reduced compound absorption. A previously examined VX concentration after 72 h of 141 ± 10 µmol/L VX could be increased to 442 ± 54 µmol/L. Finally, the respective concentrations of VX and degradation products accounted for > 90% of the initial concentration of 1000 µmol/L VX. The currently described surface modification might be a first step towards the optimization of organ-on-a-chip surfaces, facilitating a better comparability of different studies and results.