Investigation on baseline toxicity to rats based on aliphatic compounds and comparison with toxicity to fish: Effect of exposure routes on toxicity

The aim of this paper was to investigate baseline toxicity to rats and effect of exposure routes on toxicity in rats and fish. In this paper, 1588 industrial chemicals were selected to investigate baseline toxicity to rats. The results showed that rat toxicity varies around a constant for classified compounds or homologues. The toxic contributions of substituted functional groups have been calculated and alkanes were used as baseline toxicity. The toxic contributions, equal to toxic ratios (TR), show that small changes in chemical structure can result in different toxic effect in rat toxicity. However, this situation has not been observed in fish toxicity because the threshold of excess toxicity (e.g. log TR = 1) was too high to distinguish differences in toxicity. Very close critical body residues (CBRs) calculated from percentage of absorption and bioconcentration factors indicate that most of aliphatic chemicals may share the same modes of toxic action between rat and fish species. The high estimation error of bioconcentration factor calculated from computer programs for some compounds suggests that classification of excess toxicity should be based on the CBRs, rather than the TR because the TR is closely related to the exposure routes.     

The phenomenon and cause of the dose-dependent oral absorption of chlorothiazide in rats: Extrapolation to human data based on the body surface area concept

The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when the doses were related to unit body surface area (BSA) but not on unit body weight, indicating similar interspecies absorptive capacity in terms of unit BSA. This finding may be partly rationalized by marked similarities in the reported solution transit time (2–3 hr) in the small intestine as well as in the calculated gross surface area of the small intestine per unit BSA (0.163 for rat and 0.132 for human). Contrary to the previous postulation of a specific absorption site, the drug was absorbed from different regions of the GI tract with apparent 1-hr absorption rates, studied by the in situclosed-loop method, in the following rank order: jejunum (34.6%)> duodenum (32.7%)> large intestine (20.1%)>ileum (18.0%) > stomach (12.4%). Different from the commonly assumed first-order absorption process, the intestinal loop absorption was concentration-dependent, suggesting a saturable mechanism. For example, the absorption rate at 0.008 mg/mL was higher than that at 0.2mg/mL in Heal loops (61%, p<0.01) and jejunal loops (22%, p<0.1). In addition, the absorption rates at pH 6 and 7.4 were statistically identical, indicating a lack of ionization effect that is important in the passive absorption process. The solubility-limited absorption could probably be ruled out at doses below 2.55 mg/kg for rat and 125 mg for human in view of higher aqueous solubilities at 37C (e.g., 1.3 mg/mL at pH 7) found in the present study. Contrary to the previous hypothesis of low membrane permeability as a limiting factor for absorption, the intrinsic partition coefficient in 1-octanol/aqueous buffer was moderate, 0.6. Furthermore, the absorption in ileal and jejunal loops was enhanced by an apparent increase in mesenteric blood flow by caffeine. The existence of prolonged oral absorption in rats and humans is discussed. absorption in ileal and jejunal loops was enhanced by an apparent increase in mesenteric blood flow by caffeine. The existence of prolonged oral absorption in rats and humans is discussed.     

Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach

Aims

Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population.

Methods

A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients.

Results

The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h⁻¹, 2.4 l kg⁻¹ and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l⁻¹ caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function.

Conclusion

The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development.     

The reproductive toxicity of organic compounds extracted from drinking water sources on Sprague Dawley rats: An in vitro study

The safety of drinking water always causes worldwide concern. Water pollution increases with urban development and industrialization in developing countries. During recent decades, increasing numbers of environmental organic compounds have been found in aquatic environments. These organic compounds are capable of bioaccumulating to much higher concentrations in food webs and cause health effects on human beings. Reproductive impairment is one of the commonest consequences of environmental pollution. Our goal was to investigate the reproductive toxicity of organic compounds extracted from surface water samples collected in drinking water sources. This study focused on the surface water in lower Yangtze River and Taihu Lake, which act as drinking water sources of Jiangsu province, one of the most rapidly developing regions in China. We used solid‐phase extraction (SPE) to condense organic compounds by 286 times from natural surface water samples and established in vitro system to evaluate their effects on reproductive system. We found that organic compounds destroyed the plasma membrane integrity of Sertoli cells and Spermatogenic cells to a certain degree and significantly depressed viability of Sertoli cells and Spermatogenic cells as well. Accordingly, the proportion of apoptotic Sertoli cells and dead Spermatogenic cells enhanced markedly. Although viability of organic‐compound‐treated Leydig cells did not come down remarkably, testosterone production of Leydig cells decreased evidently. These results suggest that accumulated comprehensive effects of organic compounds in surface water of drinking water sources may induce spermatogenesis malfunction and reduction of testosterone production in the long term. © 2009 Wiley Periodicals, Inc. Environ Toxicol, 2010.     

两种吡罗昔康凝胶体外经皮行为的比较

目的：比较两种吡罗昔康凝胶的体外透皮吸收情况。方法：采用智能透皮试验仪对吡罗昔康凝胶进行体外经皮渗透实验,采用HPLC法测定透过离体大鼠皮肤的吡罗昔康含量。结果：样品A透皮速率达到（57.33±3.23）μg/（cm^2·h）,明显优于样品B（P〈0.01）。结论：不同厂家的吡罗昔康凝胶剂经皮性质差异显著。     

Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment

Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2‐year bioassay for TBBPA. The objective of the present study was to develop a cancer‐based and a non‐cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2‐year and 13‐week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg^?1 day^?1 based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg^?1 day^?1 based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E^?7 to 3.9 E^?6 mg kg^?1 day^?1 based on age‐adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E ^?7 to 8.4 E^?5 mg kg^?1 day^?1. Resulting margin of exposure (MOE) values were > 800 000 for non‐cancer endpoints and > 32 000 000 for cancer‐based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA. Copyright © 2015. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.     

Risk assessment of local dermal effects and skin sensitisation under the EU Chemicals Regulation REACH: a proposal for a qualitative, exposure scenario specific, approach

Within the framework of REACH, an assessment regarding local dermal effects and skin sensitisation should be performed for substances. Quantitative hazard information for these effects is often not available. Furthermore, it is difficult to relate the way in which animals are exposed in dermal toxicity studies directly to dermal exposure in practice. In the absence of quantitative information, a qualitative assessment for dermal effects is the most reasonable option. The qualitative approach as proposed in the REACH guidance recommends only general risk management measures (RMM) for three categories with a low, moderate and high identified hazard, without specifying which RMM are needed for a specific exposure scenario. We propose to differentiate frequency of exposure based on differences in activities and to compare measured and estimated local skin exposure levels with rules of thumb for evaluation of control of risks per hazard category. For workers, specific RMM regimes are assigned to each combination of hazard category and process category (PROC). For consumers, a strategy in which RMM are arranged from product-integrated measures to the use of personal protective equipment (PPE) is presented. Our approach may be transferred into automated assessment tools like Chesar and CEFIC GES.     

The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at alpha 2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2-20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1-10 mg/kg s.c.) which elicited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02-2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2-2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5-10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02-1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 micrograms/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 micrograms/kg i.m. It is concluded that the property of B-HT 920 to stimulate the 'denervated' supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.     

The impact of decreasing biodiversity on novel drug discovery: is there a serious cause for concern?

Introduction: The aim of this perspective is to discuss the current and potential situation concerning the loss of biodiversity and its current and potential effects upon the search for novel bioactive agents from natural sources, be they from marine, microbial or terrestrial environments.

Areas covered: Herein, the author covers terrestrial plants, marine organisms (but not vertebrates), and unicellular microbes from both terrestrial and marine sources. The emphasis is on the unknown effects of biodiversity perturbation and/or loss of microbes that are now realized to underlie the production of a significant number of natural products, whether they were first found in plants or marine invertebrates.

Expert opinion: From the discussion of the areas above comes the realization that we do not know what we still have. Furthermore, we cannot measure, other than in very gross terms, what we have lost. Thus, deciding how, and where geographically, one should now search for novel bioactive agents is a major and continuing problem.     

The toxicity of crude 4-methylcyclohexanemethanol (MCHM): review of experimental data and results of predictive models for its constituents and a putative metabolite

Abstract

Crude 4-methylcyclohexanemethanol (MCHM) is an industrial solvent used to clean coal. Approximately 10 000 gallons of a liquid mixture containing crude MCHM were accidently released into the Elk River in West Virginia in January 2014. Because of the proximity to a water treatment facility, the contaminated water was distributed to approximately 300 000 residents. In this review, experimental data and computational predictions for the toxicity for crude MCHM, distilled MCHM, its other components and its putative metabolites are presented. Crude MCHM, its other constituents and its metabolites have low to moderate acute and subchronic oral toxicity. Crude MCHM has been shown not to be a skin sensitizer below certain doses, indicating that at plausible human exposures it does not cause an allergic response. Crude MCHM and its constituents cause slight to moderate skin and eye irritation in rodents at high concentrations. These chemicals are not mutagenic and are not predicted to be carcinogenic. Several of the constituents were predicted through modeling to be possible developmental toxicants; however, 1,4-cyclohexanedimethanol, 1,4-cyclohexanedicarboxylic acid and dimethyl 1,4-cyclohexanedicarboxylate did not demonstrate developmental toxicity in rat studies. Following the spill, the Centers for Disease Control and Prevention recommended a short-term health advisory level of 1 ppm for drinking water that it determined was unlikely to be associated with adverse health effects. Crude MCHM has an odor threshold lower than 10 ppb, indicating that it could be detected at concentrations at least 100-fold less than this risk criterion. Collectively, the findings and predictions indicate that crude MCHM poses no apparent toxicological risk to humans at 1 ppm in household water.     

Simulated impact of a fish based shift in the population n--3 fatty acids intake on exposure to dioxins and dioxin-like compounds.

Due to the favourable health effects of LC n-3 PUFAs, marine products have been recognised as a food group of special importance in the human diet. However, seafood is susceptible to contamination by lipophilic organic pollutants. The objective of this study was to evaluate intake levels of PCDDs, PCDFs and dioxin-like PCBs, by a probabilistic Monte Carlo procedure, in relation to the recommendation on LC n-3 PUFAs given by Belgian Federal Health Council. Regarding the recommendation, two scenarios were developed differing in LC n-3 PUFAs intake: a 0.3 E% and a 0.46 E% scenario. Total exposure to dioxins and dioxin-like substances in the 0.3 E% LC n-3 PUFAs scenario ranges from 2.31 pg TEQ/kg bw/day at the 5th percentile, over 4.37 pg TEQ/kgbw/day at the 50th percentile to 8.41 pg TEQ/kgbw/day at the 95th percentile. In the 0.46 E% LC n-3 PUFAs scenario, 5, 50 and 95th percentile are exposed to 2.74, 5.52 and 9.98 pg TEQ/kgbw/day, respectively. Therefore, if the recommended LC n-3 PUFAs intake would be based on fish consumption as the only extra source, the majority of the study population would exceed the proposed health based guidance values for dioxins and dioxin-like substances.     

A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability

A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.     

Chronic haloperidol produces a time- and dose-related slowing of lick rhythm in rats: implications for rodent models of tardive dyskinesia and neuroleptic-induced parkinsonism

 In order to characterize the development of orolingual motor effects of chronic haloperidol treatment in rats, this typical neuroleptic was administered for 102 days while daily measurements of tongue movement dynamics (peak force, lick rhythm, number of licks) during water licking were recorded. After chronic haloperidol dosing (vehicle, 0.06. 0.12, 0.24 mg/kg for four separate groups) for 32 days and continuing every second or third day of the chronic dosing period, the effects of cholinergic (scopolamine: 0.05–0.20 mg/kg; trihexyphenidyl: 0.15–1.0 mg/kg) or serotonergic (ritanserin: 0.5–4.0 mg/kg; quipazine: 0.5–4.0 mg/kg) probe drugs were examined for their capacity to antagonize the alterations in licking behavior induced by haloperidol. Haloperidol dose-dependently reduced peak force and number of licks, effects which were apparent within 2 or 3 days of the start of treatment. Significant effects of haloperidol on lick rhythm first emerged on day 13 and gradually increased in magnitude through the remaining treatment period. Scopolamine, trihexyphenidyl, and quipazine reduced haloperidol’s effects on at least one measure of licking behavior. During a 7-day haloperidol withdrawal period, the four dosage groups were similar on all measures of tongue dynamics. Overall, the results exhibited features suggesting the co-occurrence of Parkinson-like and tardive dyskinesia-like effects. Received: 3 July 1997 / Final version: 22 October 1997     

Influence of paraoxon (POX) and parathion (PAT) on apoptosis: a possible mechanism for toxicity in low-dose exposure

The acute effects of poisoning with organophosphorus compounds (OPCs) are well known and have been described extensively. Most of the clinical symptoms are due to inhibition of acetylcholinesterase. Although acute OPC poisoning is a well-established clinical entity, the existence of chronic poisoning due to exposure to low levels of OPC (below the threshold required for cholinergic clinical symptoms) is a hotly debated issue. Recent studies have suggested the involvement of OPCs in apoptotic processes. However, the mechanisms by which they modulate this process are poorly investigated. In the present study we evaluated the toxic effect of different concentrations of paraoxon (POX) and parathion (PAT) in murine EL4 T lymphocytes. We examined cellular responses, including induction of apoptosis, involvement of a caspase cascade, the activity of effector caspase (caspase-3) and the biochemical and morphological changes that are the hallmarks of classical apoptosis. The results of our study indicate that at doses below IC(50) POX is a potent inducer of apoptosis, as opposed to PAT that shows little apoptotic effect.     

Safety data on 19 vehicles for use in 1 month oral rodent pre‐clinical studies: administration of hydroxypropyl‐ß‐cyclodextrin causes renal toxicity

Potential new drugs are assessed in pre‐clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl‐ß‐cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation. Copyright © 2015 John Wiley & Sons, Ltd.