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Background: Despite advanced research and great progress in understanding the chronic pancreatitis (CP) pathogenesis, no current causal treatment for the condition is available. For preclinical studies, the existence of a well-characterized CP animal model is essential. The aim of the study was to assess the impact of chronic pancreatitis on the antioxidant enzymes activity in rat blood serum and on the level of glutathione (intracellular antioxidant) in rat pancreas. Methods: The experiments were carried out on the Wistar Kyoto rats in two groups: control and study group (CP), in which chemical induction of pancreatitis with dibutyl dichloride was performed. Serum enzyme activities of amylase, lipase, catalase and superoxide dismutase were analyzed. The levels of the following biochemical parameters were also investigated: total protein, albumin, calcium, magnesium, and triglycerides. Levels of low-molecular-weight thiols: reduced (GSH) and oxidized (GSSG) glutathione, were determined in pancreatic homogenates. Results: Histopathological imaging of rat pancreatic parenchyma with induced inflammation confirmed focal lymphocytic interstitial chronic pancreatitis with fibrosis features and mild parenchymal atrophy, as well as pancreatic islets degeneration. In the CP group, we observed a statistically significant decrease in serum amylase and lipase activities and in total protein/albumin levels. Also, the elevated catalase activity was registered. In CP rats' tissues, we observed a 15-fold reduction in GSH levels. The other examined parameters remained unchanged. Clinically relevant are hypoalbuminemia and a moderate decrease in lipase activity. The described changes are most probably indicative of the impaired exocrine pancreas function, however without organ failure features. [ABSTRACT FROM AUTHOR]

Dibutyltin dichloride (DBTCl), widely used as plastic stabilizer, can cause comprehensive toxicity. The present study aims to investigate the effects of DBTCl on rat Leydig cell developmental regeneration and characterize the related mechanism. Adult male Sprague Dawley rats were randomly divided into four groups and gavaged with saline (control) or 5, 10, or 20 mg/kg/day of DBTCl consecutively for 10 days. At the end of the DBTCl treatment, all rats received a single intraperitoneal injection (i.p.,) of 75 mg/kg ethane dimethane sulfonate (EDS) to eliminate all the adult Leydig cells and to induce Leydig cell developmental regeneration. Leydig cell developmental regeneration was evaluated by measuring the levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone on days 7, 35, and 56 post-EDS. Leydig cell gene and protein expression levels, as well as cell morphology and cell counts were also carried out on day 56 post-EDS. The present study found that DBTCl significantly reduced serum testosterone levels on days 35 and 56 post-EDS, but increased serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels on day 56 at ≥ 5 mg/kg/day. The mRNA and protein levels of Leydig (Lhcgr, Scarb1, Star, Cyp11a1, Hsd17b3, and Hsd11b1) and Sertoli cells (Fshr, Amh, and Sox9) were significantly downregulated in the DBTCl-treated testes compared to the control. Immunohistochemical staining showed that DBTCl-treatment caused fewer regenerated Leydig cells and impaired Sertoli cell development and function in the testis on day 56 post-EDS. In conclusion, the present study demonstrates that DBTCl retards rat Leydig cell developmental regeneration by downregulating steroidogenesis-related enzymes at the gene and protein levels, inhibiting Leydig cell proliferation and impairing Sertoli cell function and development.

The search for new prophylactic and therapeutic drugs for the treatment of chronic pancreatitis (CP) is an urgent problem in current pancreatology. A promising direction in CP therapy may be the use of nonsteroidal anti-inflammatory drugs. Hence, the aim of the present study was to investigate the selective inhibition properties of COX-2 rofecoxib on the development of pancreas fibrosis in rats with experimental chronic pancreatitis induced by Dibutyltin dichloride (DBTC). The 60 male albino Wistar rats of our study were placed into three groups of 20 animals in each: I - the intact control; II - that which received an intraperitoneal injection (i.p.) of DBTC (6 mg/g); III - those which, 28 days after administration of DBTC (6 mg/g, i.p.), received a two-week course of treatment of rofecoxib (5 mg/kg, i.p). One day after rofecoxib treatment was completed, analysis was undertaken regarding the level of amylase, as well as the pancreatic amylase and lipase in the blood serum and the prostaglandin E2 in the pancreatic tissue. In addition, the morphological condition of the pancreas was ascertained. The obtained data suggest that administration of Rofecoxib reduces the development of fibrosis and improves the morpho-functional state of the pancreas in rats with chronic pancreatitis induced by DBTC. Thus, treatment with a selective COX-2 inhibitor could be a possible strategy for improving the clinical outcome of patients with CP.

Dibutyltin dichloride (DBTCl), widely used as plastic stabilizer, can cause comprehensive toxicity. The present study aims to investigate the effects of DBTCl on rat Leydig cell developmental regeneration and characterize the related mechanism. Adult male Sprague Dawley rats were randomly divided into four groups and gavaged with saline (control) or 5, 10, or 20 mg/kg/day of DBTCl consecutively for 10 days. At the end of the DBTCl treatment, all rats received a single intraperitoneal injection (i.p.,) of 75 mg/kg ethane dimethane sulfonate (EDS) to eliminate all the adult Leydig cells and to induce Leydig cell developmental regeneration. Leydig cell developmental regeneration was evaluated by measuring the levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone on days 7, 35, and 56 post-EDS. Leydig cell gene and protein expression levels, as well as cell morphology and cell counts were also carried out on day 56 post-EDS. The present study found that DBTCl significantly reduced serum testosterone levels on days 35 and 56 post-EDS, but increased serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels on day 56 at ≥ 5 mg/kg/day. The mRNA and protein levels of Leydig (Lhcgr, Scarb1, Star, Cyp11a1, Hsd17b3 , and Hsd11b1) and Sertoli cells (Fshr, Amh , and Sox9) were significantly downregulated in the DBTCl-treated testes compared to the control. Immunohistochemical staining showed that DBTCl-treatment caused fewer regenerated Leydig cells and impaired Sertoli cell development and function in the testis on day 56 post-EDS. In conclusion, the present study demonstrates that DBTCl retards rat Leydig cell developmental regeneration by downregulating steroidogenesis-related enzymes at the gene and protein levels, inhibiting Leydig cell proliferation and impairing Sertoli cell function and development. [ABSTRACT FROM AUTHOR]

Objectives: Heat shock protein (HSP) 70 performs a chaperoning function and protects cells against injury. Although the effect of HSPs against acute inflammatory change has been proven, the relationship between HSP70 and chronic pancreatitis remains unclear. This study aimed to investigate the protective effect of increased HSP70 expression induced by thermal stress against pancreatic fibrosis in experimental chronic pancreatitis. Materials and Methods: Two experiments to evaluate pancreatic HSP70 expression induced by thermal stress and determine the effect of increased HSP70 expression against pancreatic fibrosis were performed. To investigate HSP70 expression, rats were immersed in a warm bath and sequentially killed, and pancreatic HSP70 expression was measured. To study the effect of increased HSP70 expression, pancreatic fibrosis was induced by intravenous injection of dibutyltin dichloride (DBTC) and analyzed under repeated thermal stress. The severity of pancreatic fibrosis was measured. Results: Thermal stress significantly increased HSP70 expression in the pancreas. HSP70 expression peaked at 6-12 h after warm bathing, and the increased HSP70 expression was associated with the attenuation of pancreatic fibrosis. Although pancreatic fibrosis was induced by DBTC injection, HSP70 expression induced by repeated thermal stress diminished the severity of atrophy and fibrosis. On western blot analysis, collagen type 1 expression was diminished in the increased HSP70 expression group, but not α-smooth muscle actin expression. Conclusions: Thermal stress could increase pancreatic HSP70 expression, and induced HSP70 expression showed a protective effect against pancreatic fibrosis. Modulation of HSP70 expression could be a potential therapeutic target in the treatment of chronic pancreatitis. [ABSTRACT FROM AUTHOR]

Organometallic compounds added to organic compounds are sometimes found in contaminated sites. An organometallic compound is considered a dense nonaqueous phase liquid (DNAPL); thus, applying conventional surfactant-enhanced aqueous-based remediation may not be effective. Consequently, density-modified displacement (DMD), which is a surfactant-based remediation approach that decreases the density contrast between the remedial solution and the mobilized nonaqueous phase liquid (NAPL) through butanol (BuOH) partitioning, has been introduced. This approach converts a DNAPL into a light NAPL (LNAPL). Partitioning of each component during DMD is a vital variable in achieving efficient remediation. This study aimed to determine the effect of dibutyltin dichloride (DBT) on the distribution of each component between the aqueous phase and NAPL during the treatment process. DBT behaved as a polar organic compound and increased the polarity of the NAPL. When compared to the experiment with perchloroethylene (PCE) alone, presence of DBT increased partitioning of BuOH and the anionic surfactant from the aqueous phase to the NAPL. Moreover, presence of the anionic surfactant in the NAPL combined with a negligible level of aqueous surfactant at equilibrium in the system appeared to increase the partitioning of BuOH into the NAPL. This study's finding can be applied to the DMD technique. It can be expected that, by adding a proper polar/ionic organic compound or surfactant, the aqueous BuOH can be adequately reduced, thereby easing the transformation of the DNAPL into an LNAPL at the turning point in the DMD process. [ABSTRACT FROM AUTHOR]

Surfactant enhanced remediation is viewed as a potential method for removing organometallic compounds from contaminated aquifers. Dibutyltin dichloride (DBT), as a representative organometallic compound, was applied in sand packed columns to observe its solubilization behavior compared to that of perchloroetylene (PCE), a normal organic solvent. Ottawa sand was used as the porous media. A mixture of DBT and PCE was applied as the contaminant. The tracer study exhibited the plug flow condition with a retention time of 79.9 min. The surfactant solution was a mixture of 3.6 wt % SDHS and 0.4 wt % C16DPDS with various concentrations of CaCl2. The column experiments were carried out by single and gradient surfactant systems. The effluent exhibited a general solubilization pattern for PCE, governed by a rate limiting mechanism. However, the concentration of DBT in the effluent observed in every experiment was just a slice of its solubilization capacity. The adsorption of DBT on the sand was suspected to be the cause of the problem. The solubilization of DBT by a surfactant was ineffective at removing DBT from the contaminated media. It may be concluded that DBT exhibits the properties of both an organic and inorganic compound; it could be solubilized by a surfactant and absorbed strongly on sand. Nevertheless, the results indicate that trapped DBT could be removed by mobilization in the form of a PCE-DBT mixture and that adsorption could be prevented by a very low pH condition.

The organotin polyether derived from reaction of dibutyltin dichloride and 2,5-dimethyl-3-hexyne- 2,5-diol was rapidly synthesized employing classical interfacial polymerization in 65% yield and a chain length of 360 units. IR results are consistent with the polyether structure. Bands characteristic of the formation of the Sn-O are present and bands characteristic of the Sn-Cl are absent. F MALDI MS results in the low mass range gives ion fragment clusters to five units. Isotopic abundance matches for tin are consistent with its presence in these ion fragment clusters. In the high mass range ion fragment clusters to greater than 300 units are found. The products offer outstanding inhibition of a wide range of cancer cell lines showing inhibition of prostate, breast, and colon human cancer cell lines. The product spontaneously forms fibers. Mössbauer results are consistent with the fibers existing in a very constrained molecular environment and being present in about 50% of the product consistent with that visually observed. [ABSTRACT FROM AUTHOR]

Abstract: The harmful effects of organometallic compounds and their metabolites on the environment and human health require the development of more effective remediation methods. Surfactant enhanced remediation has been considered as a potential method for the removal of organometallic compounds; however, additional understanding is needed about the solubilization processes of these compounds. The surfactant enhanced solubilization of dibutyltin dichloride (DBT), an organometallic compound, was the focus of this research. In addition, the synergistic effects of DBT solubilization in perchloroethylene (PCE) and decane mixtures were evaluated. The results indicate that PCE and decane were solubilized into the core of these surfactant micelles in both single and mixed oil systems. DBT solubilization was limited when DBT alone was present (single oil system), and the nature of the solubilization isotherm suggests that DBT solubilization tended to occur near the micelle surface in a single oil system. DBT solubilization was found to increase when present in the PCE and decane oil mixture. PCE and decane may have facilitated the solubilization of DBT because they were solubilized in the micelle core. From this study, it may be concluded that the DBT behaves like polar oil such as dodecanol, having properties of a polar organic compound. [Copyright &y& Elsevier]

Abstract: Gabapentin, an anticonvulsant, is widely accepted as an alternative therapeutic agent for neuropathic pain and has proved to produce analgesic effects in a mouse model of visceral pain. However, it is unknown whether gabapentin is also analgesically effective in chronic pancreatitis. The aim of the present study was to investigate the role and underlying mechanisms of gabapentin in a rat model of chronic pancreatitis. Chronic pancreatitis induced by dibutyltin dichloride (DBTC) produced a marked increase in mechanical sensitivity of the abdomen after the establishment of the model. During the first day to the sixth day in the fourth week, Gabapentin was administered intraperitoneally daily at a dose of 100mg/kg. The behavioral test began 1h after drug administration. The analgesic effect of gabapentin was not evident with a single injection, but gabapentin significantly reduced the responsive frequencies to mechanical stimulation in rats with chronic pancreatitis from the third day to the end of the experiment. To explore the underlying mechanisms, the expression of α2δ-1calcium channel subunit was examined in the thoracic spinal cord (T8–11). There was no significant change in α2δ-1 level of T8–11 following the first injection. But after the sixth injection, the α2δ-1 level of T8–11 in rats with chronic pancreatitis was declined. Taken together, the present study suggested that repeated administration of gabapentin daily could reduce mechanical hypersensitivity in the upper abdomen and produce an analgesic effect in a rat model of chronic pancreatitis. The down-regulation of α2δ-1 calcium channel subunit might be one of the mechanisms underlying the analgesic effect of gabapentin. [Copyright &y& Elsevier]

Increase in the number of intrapancreatic sensory nerve fibers has been implicated in the generation of pain in chronic pancreatitis. Because some sensory neurotransmitters (e.g., substance P) are known to have proinflammatory effects, we hypothesized that denervation of intrapancreatic nerves might influence not only pain generation but also inflammation. Neonatal Lewis rats were injected with capsaicin (50 mg/kg or 0 mg/kg), a neurotoxin, to induce denervation of primary sensory neurons. When rats reached 170–190 g body weight, experimental pancreatitis was induced by a single administration of dibutyltin dichloride (7 mg/mg). The severity of pancreatitis was evaluated in both groups in the acute phase (at 3 and 7 days) and chronic phase (at 28 days). At day 7, the sensory denervation induced by neonatal capsaicin administration inhibited pancreatic inflammation on both histological (determination of interstitial edema, expansion of interlobular septa and intercellular spaces, and inflammatory cell infiltration) and biochemical (intrapancreatic myeloperoxidase activity) evaluation. Furthermore, at day 28, glandular atrophy, pseudotubular complexes, and rate of fibrosis were each significantly lower in the capsaicin-pretreated group than in the vehicle-pretreated group. Our findings provide in vivo evidence that primary sensory neurons play important roles in both acute pancreatitis and chronic pancreatic inflammation with fibrosis. [ABSTRACT FROM AUTHOR]

In this study, we examined the adverse effects of dibutyltin on initiation and maintenance of pregnancy after maternal administration during early pregnancy in mice. Following successful mating, female ICR mice were given dibutyltin dichloride (DBTCI) at 0, 7.6, 15.2, or 30.4 mg/kg bw/day by gastric intubation on days 0-3 or days 4-7 of pregnancy. Female mice were sacrificed on day 18 of pregnancy, and the pregnancy outcome was determined. After administration of DBTCI on days 0-3, the rate of nonpregnant females and the incidence of preimplantation embryonic loss were significantly increased at 30.4 mg/kg bw/day. The incidences of postimplantation embryonic loss in females given DBTCI on days 0-3 at 15.2 mg/kg and higher and on days 4-7 at 7.6 mg/kg bw/day and higher were increased. No increase in the incidence of fetuses with external malformations was observed after the administration of DBTCI on days 0-3 or days 4-7. A decline in the serum progesterone levels was detected in mice given DBTCI at 30.4 mg/kg bw/day on days 0-3 or days 4-7 of pregnancy. The data show that DBTCI adversely affects the initiation and maintenance of pregnancy when administered during early pregnancy in mice and suggest that the decline in serum progesterone levels is responsible for pregnancy failure. [ABSTRACT FROM AUTHOR]

Organotin compounds are used in a variety of applications including stabilizers, catalysts, antifouling agents, and biocides. Because of the widespread use of organotin compounds in industry and their wide range of toxic effects, it is important to measure worker exposure to specific organotin compounds. Three butyltin compounds were selected for this study—butyltin trichloride, dibutyltin dichloride, and tributyltin chloride. These three compounds are typically present in the same work environment; therefore, developing a sampling and analytical method that would allow all three butyltin compounds to be sampled and analyzed simultaneously was desired. A derivatization procedure using sodium tetraethylborate (STEB) was selected for study and validation. The validation study demonstrated that sampling using the Occupational Safety and Health Administration (OSHA) Versatile Sampler (OVS) with XAD-2 resin sorbent and analysis using gas chromatography/flame photometric detection (GC/FPD) can be used to evaluate worker exposures to specific butyltin chlorides over the range of 5 to 270 µg/m3 collected at a flowrate of 0.25 L/min over a 3-hour period for a 45-L air sample. Breakthrough studies at 1.5 times the occupational exposure guideline (OEG) of 0.05 mg/m3 showed that samples could be collected at flowrates up to 0.5 L/min for 12 hours without breakthrough. The 14-day storage stability study showed apparent degradation of tributyltin and monobutyltin within a 3-day storage period at both ambient and refrigerated temperatures. There was no further degradation from 3 to 14 days. The stability of dibutyltin was unaffected by storage condition over the 14-day storage study. Subsequent stability studies incorporating a spiking solution control sample were conducted extending the stability study out to 27 days. These data show that all three butyltins were stable at either ambient or refrigerated conditions. [ABSTRACT FROM AUTHOR]

In our previous study, dibutyltin dichloride (DBTCl) caused preimplantation embryonic loss and postimplantation embryonic loss in rats following administration at 7.6 mg/kg and above on Days 0–3 and at 3.8 mg/kg and above on Days 4–7 of pregnancy, respectively. This study was designed to assess the effects of DBTCl on uterine function as a cause of early embryonic loss using pseudopregnant rats. DBTCl was given orally to pseudopregnant rats at 3.8, 7.6 or 15.2 mg/kg on pseudopregnant day (PPD) 0–3 or on PPD 4–7. The decidual cell response was induced by bilateral uterine scratch on PPD 4. The uterine weight on PPD 9 served as an index of uterine decidualization. Uterine weight and serum progesterone levels on PPD 9 were significantly decreased after administration of DBTCl at 7.6 mg/kg and above on PPD 0–3 and PPD 4–7. DBTCl had no effect on the serum estradiol levels and number of corpora lutea. Administration of progesterone reversed the suppression of uterine decidualization in rats given DBTCl on PPD 0–3. It can be concluded that DBTCl suppresses the uterine decidual cell response and decreases progesterone levels, and these effects are responsible for early embryonic loss due to DBTCl exposure. [Copyright &y& Elsevier]

We recently reported that hyperthermia induces pancreatic expression of heat shock proteins (HSPs), particularly HSP70 isoforms, and protects against cerulein pancreatitis. We have now studied whether a double hyperthermia amplifies these effects and whether hyperthermia also protects against dibutyltin dichloride (DBTC)-induced pancreatitis. A further aim was to examine whether hyperthermia induces changes in transforming growth factor-beta1 (TGF-beta1). Following pretreatment without or with a single or double hyperthermia, pancreatitis was induced by application of cerulein or DBTC. Pancreatic HSP and TGF-beta1 expression were studied by immunoblotting. Pancreas injury was assessed by light microscopy and serum pancreatic enzyme activity. Hyperthermia as well as DBTC induced HSP72, whereas cerulein did not. A double hyperthermia led to a further increase in HSP72 compared to a single heat stress. In both models, hyperthermia significantly reduced pancreatic injury. Although a double hyperthermia slightly decreased the severity of cerulein pancreatitis compared to a single heat treatment, an improved pancreas protection against DBTC cytotoxicity was not achieved. We also found that hyperthermia induces the expression of TGF-beta1. In conclusion, hyperthermia preconditioning exerts protective effects against two pathophysiologically different types of pancreatitis by a mechanism that involves the up-regulation of HSP70 isoforms as well as TGF-beta1. [ABSTRACT FROM AUTHOR]

1 Dialkyltin compounds have been widely used in industry and agriculture, mainly as biocides, catalysts and plast stabilizer. In dependence on the length of the alkyl chains these organotins exert toxic effects on the immune system, the bile duct, liver and pancreas. It has been supposed that similar to organoarsenic the toxicity of the dialkyltin compounds is related to reactions with biological dithiol groups. Therefore, in the present study, the antidotal effects of 2,3-dimercapto-propane-1-sulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the organotoxic effects of dibutyltin dichloride (DBTC, single administration of 27 μmol kg[sup -1] b.w. i.v.) in rats were studied using different doses (100 and 500 μmol kg[sup -1] b.w.) and routes of administration (i.p. and p.o.) of both chelators. Several parameters of organotoxicity (thymus weight and cellularity, bile duct diameter, histological lesions of pancreas and liver, activities of amylase, lipase and alkaline phosphatase, bilirubin and hyaluronic acid in serum) were measured from 6 h to 8 weeks. 2 DMPS and DMSA diminished the DBTC induced bile duct, pancreas and liver lesions stronger than the thymus atrophy. Moreover, the development of a fibrosis of the pancreas and a cirrhosis of liver several weeks after single administration of DBTC to rats was inhibited by DMPS and DMSA. The antidotal effects on serum parameter were observed after both administration routes of the chelators. DMPS was more effective than DMSA in most measured parameters. The decrease in the biliary excretion of organotin by DMPS and DMSA seems to be the reason for the pronounced protective effects of DMPS and DMSA on bile duct, pancreas and liver. 3 For the treatment of poisonings with dibutyltin compounds, the administration of DMPS or DMSA can be recommended. [ABSTRACT FROM AUTHOR]

The present study was done to determine the additional influence of daily ethanol intake (15% in drinking water ad libitum) on long-term toxic effects of a single administration of dibutyltin dichloride (DBTC, 8 mg/kg b.w. i.v.) in pancreas and liver of rats. Pathohistological changes in pancreas, bile duct and liver as well as pathobiochemical parameters of pancreatitis (amylase and lipase activity), liver lesions (alkaline phosphatase activity and bilirubin) and fibrosis (hydroxyproline and hyaluronic acid) were measured 1 day and 1 to 24 weeks after DBTC- and DBTC/ethanol administration. DBTC alone induced in rats an acute interstitial pancreatitis as well as acute bile duct and liver lesions in the early experimental phase. Later on, the acute inflammatory processes in pancreas and liver took a chronic course resulting in pancreatic fibrosis and liver cirrhosis. Ethanol increased the toxic effects of DBTC on pancreas and liver during the acute and chronic course. In the acute phase lasting 1 day to 2 weeks, ethanol enhanced the DBTC toxicity on acinar cell and bilio-pancreatic duct epithelium as well as the formation of obstructive ductal plugs by necrotic cell debris. The obstruction and cholestasis in the DBTC/ethanol-group were significantly stronger as in the DBTC-group. The significant increase of hydroxyproline in urine and hyaluronic acid in serum of the DBTC/ethanol treated rats after 12 to 24 weeks was connected with a more severe chronic inflammatory fibrosis in pancreas and liver in comparison to the DBTC-treated group. [ABSTRACT FROM AUTHOR]

Programs including the ToxCast project have generated large amounts of in vitro high‒throughput screening (HTS) data, and best approaches for the interpretation and use of HTS data, including for chemical safety assessment, remain to be evaluated. To fill this gap, we conducted case studies of two indirect food additive chemicals where ToxCast data were compared with in vivo toxicity data using the RISK21 approach. Two food contact substances, sodium (2-pyridylthio)-N-oxide and dibutyltin dichloride, were selected, and available exposure data, toxicity data, and model predictions were compiled and assessed. Oral equivalent doses for the ToxCast bioactivity data were determined by in-vitro in-vivo extrapolation (IVIVE). For sodium (2-pyridylthio)-N-oxide, bioactive concentrations in ToxCast assays corresponded to low- and no-observed adverse effect levels in animal studies. For dibutyltin dichloride, the ToxCast bioactive concentrations were below the dose range that demonstrated toxicity in animals; however, this was confounded by the lack of toxicokinetic data, necessitating the use of conservative toxicokinetic parameter estimates for IVIVE calculations. This study highlights the potential utility of the RISK21 approach for interpretation of the ToxCast HTS data, as well as the challenges involved in integrating in vitro HTS data into safety assessments. • We conducted risk assessment case studies comparing ToxCast data with in vivo toxicity data for two indirect food additives. • For one compound, concentrations eliciting bioactivity in ToxCast were similar to doses causing in vivo toxicity. • Pharmacokinetic data gaps for the other compound led to greatly varying oral equivalent doses derived from the ToxCast data. • There is potential for incorporation of in vitro data in chemical safety risk assessment, though many challenges remain. [ABSTRACT FROM AUTHOR]