Exploring the half-life of glyphosate in human urine samples

Background

The International Agency for Research on Cancer (IARC) has recently classified glyphosate as a Group 2A ‘probably carcinogenic to humans’. Due to this carcinogenic classification and resulting international debate, there is an increased demand for studies evaluating human health effects from glyphosate exposures. There is currently limited information on human exposures to glyphosate and a paucity of data regarding glyphosate's biological half-life in humans.

Interpreting in vitro developmental toxicity test battery results: The consideration of toxicokinetics

In the EU collaborative project ChemScreen an alternative, in vitro assay-based test strategy was developed to screen compounds for reproductive toxicity. A toxicokinetic modeling approach was used to allow quantitative comparison between effective concentrations in the in vitro test battery and observations of developmental toxicity in vivo. This modeling strategy is based on (1) the definition of relevant observations of toxicity in vivo, (2) simulation of the corresponding systemic concentrations in vivo by toxicokinetic modeling, and (3) correction for differences in protein binding and lipid partitioning between plasma and in vitro test media. The test results of a feasibility study with a number of known reproductive toxicants has been described previously (Piersma et al. [15]). In the present paper, we take a more detailed look at the toxicokinetics of these compounds, and add the analysis of some compounds from subsequent studies. We discuss how the consideration of toxicokinetics allowed comparison between test systems with differing test medium composition, has helped to interpret the in vitro findings in light of in vivo observations, and to gain confidence in the predictive value of the test battery outcomes. The same toxicokinetic modeling strategy, in reverse order, can now be used for risk assessment purposes to predict toxic doses in vivo from effective concentrations in vitro.     

Embryo–fetal exposure and developmental outcome of thalidomide following oral and intravaginal administration to pregnant rabbits

Studies in pregnant rabbits were conducted to evaluate if there are any differences in the uptake of thalidomide into the intrauterine compartment and developmental toxicity risk following oral and intravaginal administration. Thalidomide concentrations in maternal plasma, yolk sac cavity (YSC) fluid and embryo following intravaginal administration were 2- to 7-fold lower than their respective levels after oral administration. Ratios of thalidomide concentration in YSC fluid to maternal plasma were similar between these two routes, indicating no difference in uptake into the intrauterine compartment. A rabbit embryo–fetal development study using oral and intravaginal thalidomide administration at 2 mg/kg/day (a dose >10,000-fold higher than the expected amount of thalidomide in human semen) did not result in any developmental abnormalities. These data demonstrated no preferential transfer mechanism of thalidomide from vagina to conceptus, and no additional embryo–fetal developmental toxicity risks with thalidomide exposure via the vaginal route.     

Biomarkers for monitoring transfluthrin exposure: Urinary excretion kinetics of transfluthrin metabolites in rats

The urinary excretion kinetics of a fluorine-containing pyrethroid transfluthrin [(2,3,5,6-tetrafluorophenyl)methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate], which is widely used recently as mosquito repellents, was examined in rats to search for urinary metabolites suitable as biomarkers for monitoring transfluthrin exposure of the general population. After a single dose of 26, 64, 160 or 400 mg/kg body weight of transfluthrin had been administered intraperitoneally to male Sprague-Dawley rats, their urine was collected periodically for one week. Three major urinary transfluthrin metabolites were measured: 2,3,5,6-tetrafluorobenzyl alcohol, 2,3,5,6-tetrafluorobenzoic acid and 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid. The kinetics was evaluated by moment analysis of the urinary excretion rate of the metabolites versus time curves.The urinary excretion amounts of these three metabolites were estimated to be proportional to the absorption amounts of transfluthrin over a wide exposure range. Urinary 2,3,5,6-tetrafluorobenzoic acid was considered to be an optimal biomarker for monitoring transfluthrin exposure.     

注射用伏立康唑前药的遗传及生殖毒性研究

目的 研究注射用伏立康唑前药(Voriconazole prodrug,VP)的遗传及生殖毒性.方法 分别采用Ames试验、中国仓鼠肺细胞(CHL)染色体畸变试验、小鼠骨髓微核试验,观察VP的遗传毒性,并通过伴随毒动学试验了解其血浆暴露量;生殖毒性研究了注射用VP对SD大鼠胚胎-胎仔发育毒性的影响,于SD大鼠妊娠第6～ 15天连续iv给药(30、60、120 mg· kg-1·d-1),于妊娠第20天剖检,分析其生殖毒性.结果 遗传毒性的Ames试验、CHL试验和微核试验中,结果均显示为阴性;伴随毒动学试验表明:受试物在小鼠体内呈线性消除;胚胎-胎仔发育毒性试验中,受试物高剂量组中胎鼠头颅骨和/或胸骨异常的数量与溶媒对照组相比显著增加.结论 注射用VP未见明显遗传毒性;受试物在120 mg·kg-1剂量下对胎鼠骨骼发育有一定的毒性作用,未见其他生殖毒性.     

Tissue distribution of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat

Understanding tissue distribution and clearance of nanomaterials following different routes of exposure is needed for risk assessment. F344 female rats received single or multiple exposures to 20 nm, 100 nm or 1000 nm latex fluorospheres by intravenous (i.v.) injection or oral pharyngeal aspiration into the airways. The presence of fluorospheres in tissues was assessed up to 90–120 days after the final dose. Blood, perfusion fluid, bone marrow, brain, eyes, feces, gut, heart, kidney, liver, lung, muscle, skin, spleen, thymus, tongue, urine and uterus plus ovaries were collected for analysis. Liver, spleen and lung were the greatest tissue depots for all particles following i.v. injection. The proportion of 100 nm and 1000 nm but not 20 nm spheres significantly increased in the spleen over time. Lung was the greatest tissue depot for all particles following single or repeat airway exposure. Greater than 95% of 1000 nm spheres that were recovered were in the lung in contrast to 70–80% of 20 nm spheres or 89–95% of 100 nm spheres. All 3 sizes were found in gut or gut + feces 1–7 days after lung exposure. The thymus was the largest extra-pulmonary depot for the particles; up to 25% of recovered 20 nm particles were in the thymus up to 4 months after exposure compared to 6% of 100 nm particles and 1–3% of 1000 nm particles. A small proportion of 20 nm particles were detected in kidney following both acute and repeat airway exposure. Low numbers of particles were found in the circulation (blood, perfusion), bone marrow, brain, heart, liver and spleen but not in eye, muscle, skin, tongue, ovaries, uterus or urine. These data show that the tissue targets of nano- and micron-sized spheres are very similar whether exposure occurs systemically or via the airways while the proportion of particles in some tissues and tissue clearance varies based on particle size.     

Toxicity and toxicokinetics of metformin in rats

Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage for 13 weeks. Administration of ≥ 900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given ≥ 600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses ≥ 600 mg/kg/day. There were no significant sex differences in mean AUC_0-24 or C_max nor were there significant differences in mean AUC_0-24 or C_max following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC_0-24 = 41.1 μg h/mL; mean C_max = 10.3 μg/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.     

氚标记二氯硝基酚铵盐在实验动物体内的毒代动力学研究

作者采用放射性同位素技术研究了H~3-DCNPA经口染毒小鼠后,在体内的吸收、分布、排泄情况。结果显示血毒浓度时程曲线拟合,以二室开放模式为最优。吸收速率常数(Ka)为4.840h~1,吸收相、分布相、消除相半衰期(T1/2Ka,T1/2α,T1/2β)分别为0.143,0.791,13.96h。峰时Tmax为0.565h,峰浓度Cmax为0.67μg/ml。排泄率常数Ke为0.094h~1。染毒大鼠的排泄实验表明72小时后,可排出98%,粪尿排泄比例相近。~3H-DCNPA可经过大鼠胎盘屏障,但仍有一定的阻留。     

Toxicokinetics of p-tert-octylphenol in male Wistar rats

Only weak oestrogenic activity has been reported for p-alkylphenols compared with the physiological hormone 17β-estradiol. Despite the low potency, there is concern that due to bioaccumulation oestrogenically efficient blood levels could be reached in humans exposed to trace levels of p-alkylphenols. To address these concerns, toxicokinetic studies with p-tert-octylphenol [OP; p-(1,1,3,3-tetramethylbutyl)-phenol] as a model compound have been conducted in male Wistar rats. OP blood concentrations were determined by GC-MS in rats receiving either single oral (gavage) applications of 50 or 200mg OP/kg body wt or a single intravenous injection of 5mg/kg body wt. The OP blood concentration was ∼1970ng/ml immediately after a single intravenous application, decreased rapidly within 30 min, and was no longer detectable 6–8h after application. The curve of blood concentration vs time was used to calculate an elimination half-life of 310min. OP was detected in blood as early as 10min after gavage administration, indicating rapid initial uptake from the gastrointestinal tract; maximal blood levels reached 40 and 130ng/ml after applications of 50 and 200mg/kg, respectively. Using the area under the curve (AUC) of blood concentration vs time, low oral bioavailabilities of 2 and 10% were calculated for the 50 and 200mg/kg groups, respectively. OP toxicokinetics after repeated administration was investigated in male Wistar rats receiving daily gavage administrations of 50 or 200mg OP/kg body wt for 14 consecutive days. Profiles of OP blood concentration vs time determined on day 1 and day 14 were similar, indicating that repeated oral gavage administration did not lead to increased blood concentrations. Another group of rats received OP via drinking water saturated with OP (∼8mg/l, corresponding to a mean daily dose of ∼800μg/kg) over a period of up to 28 days. OP was not detected in any blood sample from animals treated via drinking water (detection limit was 1–5ng/ml blood). OP concentrations were also analysed in tissues obtained from the repeated gavage (14 days) and drinking water groups (14 and 28 days). In the 50mg/kg group, low OP concentrations were detected in fat and liver from some animals at average concentrations of 10 and 7ng/g tissue, respectively. OP was not detected in the other tissues analysed from this group. In the 200mg/kg group, OP was found in all tissues analysed except testes (fat, liver, kidney, muscle, brain and lung had average concentrations of 1285, 87, 71, 43, 9 and 7ng/g tissue, respectively). OP was not detected in tissues of animals receiving OP via drinking water for 14 or 28 days, except in muscle and kidney tissue of one single animal receiving OP for 14 days. Using rat liver fractions it was demonstrated that OP was conjugated via glucuronidation and sulphation in vitro. A V _max of 11.24 nmol/(min * mg microsomal protein) and a K _m of 8.77μmol/l were calculated for enzyme-catalysed OP glucuronidation. For enzyme-catalysed sulphation, a V _max of 2.85nmol/(minT15*mg protein) and a K _m of 11.35μmol/l were calculated. The results indicate that OP does not bioaccumulate in rats receiving low oral doses, in agreement with the hypothesis of a rapid first-pass elimination of OP by the liver after oral ingestion, via glucuronidation and sulphation. Only if these detoxification pathways are saturated may excessive doses lead to bioaccumulation. Received: 22 March 1996/Accepted: 12 June 1996     

Dose and route dependency of metabolism and toxicity of chloroform in ethanol-treated rats

 The effects of a single dose of ethanol on the metabolism and toxicity of chloroform administered to rats per os (p.o.), intraperitoneally (i.p.), or by inhalation (inh) at different doses were investigated. Rats that had been given either ethanol (2 g/kg) or vehicle (water) alone at 4 p.m. on the previous day were challenged with chloroform at 10 a.m. p.o. (0, 0.1, 0.2, or 0.4 g/kg), i.p. (0, 0.1, 0.2, or 0.4 g/kg), or inh (for 6 h each at 0, 50, 100, or 500 ppm). The ethanol treatment, which had no influence on the intake of food and water, increased chloroform metabolism in vitro about 1.5-fold with no significant influence on liver glutathione content. The treatment had a dose-dependent effect on the metabolism and toxicity of chloroform, and the effect differed depending on the route of administration. Compared at the same dose level, the area under the curve (AUC) of blood chloroform concentration was invariably smaller following p.o. than i.p. administration. In accordance with this, chloroform administered p.o. caused more deleterious hepatic damage than the same amount of chloroform administered i.p. Although ethanol treatment had no significant influence on the AUC at any dose by any route of administration, the toxicity of p.o.-administered chloroform was significantly higher in ethanol-treated rats than in control rats at a dose as low as 0.1 g/kg, whereas no significant difference was observed in toxicity between both groups of rats at such a low dose administered i.p. When rats were exposed inh to air containing chloroform vapor, ethanol consumption had no effect on hepatotoxicity until the exposure concentration was raised to 500 ppm, a finding which suggests that a single dose of ethanol (2 g/kg) affects the toxicokinetics of inhaled chloroform in rats only at a concentration as high as 500 ppm. Received: 6 December 1993 / Accepted: 25 May 1994