Pharmacokinetic Study of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles HY-088 in Rats.

BACKGROUND AND OBJECTIVE: HY-088 injection is an ultrasmall superparamagnetic iron oxide nanoparticle (USPIOs) composed of iron oxide crystals coated with polyacrylic acid (PAA) on the surface. The purpose of this study was to investigate the pharmacokinetics, tissue distribution, and mass balance of HY-088 injection. METHODS: The pharmacokinetics of [55Fe]-HY-088 and [14C]-HY-088 were investigated in 48 SD rats by intravenous injection of 8.5 (low-dose group), 25.5 (medium-dose group), and 85 (high-dose group) mg/100 µCi/kg. Tissue distribution was studied by intravenous injection of 35 mg/100 µCi/kg in 48 SD rats, and its tissue distribution in vivo was obtained by ex vivo tissue assay. At the same time, [14C]-HY-088 was injected intravenously at a dose of 25.5 mg/100 µCi/kg into 16 SD rats, and its tissue distribution in vivo was studied by quantitative whole-body autoradiography. [14C]-HY-088 and [55Fe]-HY-088 were injected intravenously into 24 SD rats at a dose of 35 mg/100 µCi/kg, and their metabolism was observed. RESULTS: In the pharmacokinetic study, [55Fe]-HY-088 reached the maximum observed concentration (Cmax) at 0.08 h in the low- and medium-dose groups of SD rats. [14C]-HY-088 reached Cmax at 0.08 h in the three groups of SD rats. The area under the concentration-time curve (AUC) of [55Fe]-HY-088 and [14C]-HY-088 increased with increasing dose. In the tissue distribution study, [55Fe]-HY-088 and [14C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes of both female and male rats. In the mass balance study conducted over 57 days, the radioactive content of 55Fe from [55Fe]-HY-088 was primarily found in the carcass, accounting for 86.42 ± 4.18% in females and 95.46 ± 6.42% in males. The radioactive recovery rates of [14C]-HY-088 in the urine of female and male rats were 52.99 ± 5.48% and 60.66 ± 2.23%, respectively. CONCLUSIONS: Following single intravenous administration of [55Fe]-HY-088 and [14C]-HY-088 in SD rats, rapid absorption was observed. Both [55Fe]-HY-088 and [14C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes. During metabolism, the radioactivity of [55Fe]-HY-088 is mainly present in the carcass, whereas the 14C-labeled [14C]-HY-088 shell PAA is eliminated from the body mainly through the urine.

Cord Blood Manganese Concentrations in Relation to Birth Outcomes and Childhood Physical Growth: A Prospective Birth Cohort Study.

Gestational exposure to manganese (Mn), an essential trace element, is associated with fetal and childhood physical growth. However, it is unclear which period of growth is more significantly affected by prenatal Mn exposure. The current study was conducted to assess the associations of umbilical cord-blood Mn levels with birth outcomes and childhood continuous physical development. The umbilical cord-blood Mn concentrations of 1179 mother-infant pairs in the Sheyang mini birth cohort were measured by graphite furnace atomic absorption spectrometry (GFAAS). The association of cord-blood Mn concentrations with birth outcomes, and the BMI z-score at 1, 2, 3, 6, 7 and 8 years old, were estimated separately using generalized linear models. The relationship between prenatal Mn exposure and BMI z-score trajectory was assessed with generalized estimating equation models. The median of cord-blood Mn concentration was 29.25 µg/L. Significantly positive associations were observed between Mn exposure and ponderal index (ß, regression coefficient = 0.065, 95% CI, confidence interval: 0.021, 0.109; p = 0.004). Mn exposure was negatively associated with the BMI z-score of children aged 1, 2, and 3 years (ß = -0.383 to -0.249, p < 0.05), while no significant relationships were found between Mn exposure and the BMI z-score of children at the age of 6, 7, and 8 years. Prenatal Mn exposure was related to the childhood BMI z-score trajectory (ß = -0.218, 95% CI: -0.416, -0.021; p = 0.030). These results indicated that prenatal Mn exposure was positively related to the ponderal index (PI), and negatively related to physical growth in childhood, which seemed most significant at an early stage.

Adverse Associations of both Prenatal and Postnatal Exposure to Organophosphorous Pesticides with Infant Neurodevelopment in an Agricultural Area of Jiangsu Province, China.

BACKGROUND: Prenatal exposure to organophosphorous (OP) pesticides has been found to be associated with adverse effects on child neurodevelopment, but evidence on potential effects induced by both prenatal and postnatal OP exposure in infants is limited. OBJECTIVES: Our aim was to investigate the associations of both prenatal and postnatal OP exposure with birth outcomes and infant neurodevelopment. METHODS: Exposure to OP in 310 mother-infant pairs was assessed by measuring dimethylphosphate (DM), diethylphosphate (DE), and total dialkylphosphate (DAP) metabolites in urines from pregnant women and their children at 2 years of age. The Gesell Developmental Schedules was administered to examine neurodevelopment of 2-year-old children. RESULTS: Based on the Gesell Developmental Schedules, the proportions of children with developmental delays were < 6%. Adverse associations between head circumference at birth and prenatal OP exposure were demonstrated. Both prenatal and postnatal OP exposure was significantly associated with increased risk of being developmentally delayed. Specifically, odds ratio (OR) value for prenatal DEs was 9.75 (95% CI: 1.28, 73.98, p = 0.028) in the adaptive area, whereas in the social area, OR values for postnatal DEs and DAPs were 9.56 (95% CI: 1.59, 57.57, p = 0.014) and 12.00 (95% CI: 1.23, 117.37, p = 0.033), respectively. Adverse associations were observed only in boys, not in girls. CONCLUSIONS: Both prenatal and postnatal OP exposure may adversely affect the neurodevelopment of infants living in the agricultural area. The present study adds to the accumulating evidence on associations of prenatal and postnatal OP exposure with infant neurodevelopment. CITATION: Liu P, Wu C, Chang X, Qi X, Zheng M, Zhou Z. 2016. Adverse associations of both prenatal and postnatal exposure to organophosphorous pesticides with infant neurodevelopment in an agricultural area of Jiangsu Province, China. Environ Health Perspect 124:1637-1643; http://dx.doi.org/10.1289/EHP196.

[Environmental safety assessment on the new super absorbent polymers applied into a soil-Chinese cabbage system].

Super absorbent polymers (SAPs), a new water retention material, have a potential for application in water-saving agricultural production. In this study, we investigated the effects of SAPs, synthesized from natural plant extracts, on Chinese cabbage fresh weight, soil water content, soil water stable aggregates, soil microbial biomass (carbon) and soil microbial respiration under three water conditions (excessive, normal and deficient) and two SAPs application strategies (bulk treatment and spraying treatment). The results showed that the SAPs significantly promoted the soil water content, water-stable aggregates (> 0.25 mm) and the soil microbial activities, especially under the water deficient conditions. Meanwhile, SAP application strategy was of great significance to the effects on Chinese cabbage and soil properties. Compared with the control treatment under normal water condition, spraying treatment of Jaguar C (S-JC) could reduce irrigation water amount by about 25% without reducing the crop production. Furthermore, compared with the control treatment under the same water condition with S-JC (deficient), it could increase Chinese cabbage production by 287%. Thus, SAPs is an environmental friendly water-saving technique in agricultural production.

Assessment of chlorpyrifos exposure and absorbed daily doses among infants living in an agricultural area of the Province of Jiangsu, China.

PURPOSE: Chlorpyrifos (CPF) is one of the most widely used organophosphorous pesticides in China. However, few reports on CPF pesticide exposure and body burden of infants at 2 years of age in China are available. The aim of this study was to assess the exposure level and the absorbed daily dose (ADD) of CPF among infants from an agricultural area of Jiangsu, China, and determine whether the infants' estimated dose exceeds the recommended reference dose (RfD) and the population adjusted dose (PAD) set by U.S. Environmental Protection Agency (EPA). METHODS: In our study, 364 infants at 2 years of age who lived in the agricultural area of Jiangsu Province (China) were enrolled into the biomonitoring study from June 2011 to January 2012. CPF exposure was estimated based on both questionnaire survey and measured results of urinary metabolite 3,5,6-trichloro-2-pyridinol (TCPy) of CPF by high-performance liquid chromatography. Furthermore, the ADD of CPF among infants was also evaluated and compared with the RfD and the PAD values issued by EPA. RESULTS: Urinary TCPy was detected in more than 70 % of the urine samples among 364 infants. The unadjusted and creatinine-adjusted geometric means in these subjects for TCPy were 1.33 µg/L and 6.73 µg/g Cre., respectively. Infants lived nearby (100 m distance) plantations or green parks present significantly higher levels of urinary TCPy than those lived far away (p = 0.045). Urinary TCPy levels were also significantly higher in infants who had frequent hand-to-mouth activities than those with less frequency (p = 0.037). Urinary TCPy concentrations in the infants at 2 years of age in Jiangsu were lower than those in the children at 2-6 years of age in the USA. The median estimated ADD of CPF in this study (0.07 µg/kg/day) was much lower than the acute and chronic RfDs (5 and 0.3 µg/kg/day, respectively) announced by EPA, but higher than the chronic PAD (cPAD) (0.03 µg/kg/day) for children. Additionally, the 75th percentile of the estimated ADD in our study was 2.5 times as much as the cPAD from EPA, even assuming only half of the TCPy amount from CPF exposure. CONCLUSIONS: Our findings revealed that infants at 2 years of age in Jiangsu of China were widely exposed to CPF pesticide. The estimated ADD probably suggested that about 25 % of the enrolled infants were at potential risk of pesticide exposure, which warned of urgency to eliminate the potential exposure risk to infants living in agricultural areas of China.

Urinary metabolite levels of pyrethroid insecticides in infants living in an agricultural area of the Province of Jiangsu in China.

Pyrethroid insecticides are extensively and increasingly applied in agricultural and residential environments in China. Children's exposure to pesticides attracted global concerns because of their particular vulnerability. Several studies have reported residual pyrethroid levels in urine both in adults and in children. However, few published data focused on very young infants. The study aimed to assess exposure to pyrethroid insecticides in young infants and investigate the potential influence factors on pyrethroid exposure levels. Data on pyrethroids exposure was based on questionnaire items and measurement of urinary metabolite levels among 481 infants. We detected pyrethroid metabolites of 3-phenoxybenzoic acid (3-PBA), cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cis-DCCA and trans-DCCA) in urine using a gas chromatography-mass spectrometry method. Median values for urinary pyrethroid metabolites in these infants were 0.39 µgL(-1) for 3-PBA, 0.18 µgL(-1) for cis-DCCA, 0.92 µgL(-1) for trans-DCCA, respectively. About 60.9% of the infants had urinary concentrations of three pyrethroid metabolites that were above the level of 0.10 µgL(-1) (limit of detection, LOD). These findings of the urinary metabolites were comparable or slightly higher than those children from the other countries. From questionnaire, we learned that more than 70% of households reported that they or family members had applied mosquito repellents in infants. Above data indicated the need to assess the potential adverse effects of pyrethroids exposure on infants in order to take adequate measures to protect them from pesticide exposures during early childhood.

Urinary pyrethroid metabolites among pregnant women in an agricultural area of the Province of Jiangsu, China.

Pyrethroid pesticides are widely used throughout the world in agriculture to protect crops and in public health to control diseases. Of particular concern is exposure of pregnant women and their fetuses because little is known about the potential developmental hazards of such exposure. Several studies have detected internal pyrethroid exposure in urine both in adults and children, but few published data are available on metabolites in pregnant women. The present paper provides data on pyrethroid pesticides exposure based on questionnaire items and measurement of maternal urinary metabolite levels among 1149 pregnant women living in agricultural area of Jiangsu Province, China in 2009-2010, none of which reported occupational exposure to pyrethroid insecticides during pregnancy. To assess exposure to pyrethroid pesticides, urine specimens were analyzed for three main metabolites of 3-phenoxybenzoic acid (3-PBA), cis-and-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cis-DCCA and trans-DCCA) using a gas chromatography-mass spectrometry method. The limits of detection for three pyrethroid metabolites were 0.1µg/L. All pyrethroid metabolites were found in more than 94.0% of the urine samples. Median unadjusted and creatinine-adjusted values for urinary pyrethroid metabolites in these females were 1.01µg/L and 1.55µg/g Cre for 3-PBA, 0.44µg/L and 0.69µg/g Cre for cis-DCCA, 1.17µg/L and 1.86µg/g Cre for trans-DCCA, respectively. About half (45.5%) of women reported that they or family members had applied commercially available indoor insecticides during pregnancy. Both the questionnaire and laboratory data revealed that exposure to pyrethroid pesticides was considerably widespread in our subjects. The median values of urinary metabolites in the present study were about 4-10 times higher as those of general population from the developed countries. Interestingly, we found there was a temporal season variation tendency in different months. Especially, the levels of urinary metabolites in summer were significant higher than those in winter. These data indicated the need to assess the potential adverse effects of pyrethroid pesticides exposure on fetuses and infants in order to take adequate measures to protect pregnant women from pesticide exposures during pregnancy.

[Impact of prenatal pyrethroid exposure on neurodevelopment of one-year old infants].

OBJECTIVE: To investigate the impact of prenatal exposure to pyrethroid pesticides on neurodevelopment and behavior in a group of one-year old infants. METHODS: Three metabolites of pyrethroids (cis-Cl2CA, trans-Cl2CA and 3-PBA) in urine samples of 301 pregnant women enrolled from somewhere of Jiangsu Province were detected, The anthropometrics and the neurodevelopment of their 1-year old infants were assessed using DST scales. The mothers were consent informed before the study. RESULTS: Three metabolites of pyrethroid were detected in 95% of urine samples. The infants were divided into high, medium or low exposure group by the level of pyrethroid in their mothers' urine detected during pregnancy. The difference of neurodevelopment index (DQ) among three groups of one-year old children was significant (P < 0.05), and the association of pyrethroid exposure with neurodevelopment was verified by multiple liner regression analysis (beta = - 0.1453, P < 0.05). CONCLUSION: Prenatal exposure to elevated levels of pyrethroid pesticides was associated with reduced neurodevelopment of infants in this population.

[Use of threshold of toxicological concern for chemical substances safety assessment].

The threshold of toxicological concern (TTC) approach is a risk assessment tool of toxicology. When the exposure dose of human body is below the TTC of chemicals, the likelihood of that chemical causing negative influence on the human health is very low. Earliest, TTC approach was used in the risk assessment of in the respect of the food packing materials. Currently, TTC approach is used for safety assessment in the fields of food packing material, flavoring agents, medicine, industry chemicals, cosmetics, and etc. TTC approach provides useful assessment tool for the safety evaluation for the chemical substances.

[Advance of study on the detoxification of the microcystin].

Contamination of water on toxic blooms of cyanobacteria has occurred in many regions of the world and could be a serious public health problem. It is hard to degrade all the microcystins by using ordinary waste water treatment process, so it is increasingly urgent to develop a new technology to deal with them. In this article the current ways of effectively removing microcystin toxins were reviewed.

Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice.

OBJECTIVE: To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice. METHODS: Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. RESULTS: MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice. CONCLUSION: Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.

Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats.

OBJECTIVE: Some animal models apply morphine in the drinking water to generate addiction, but related reports are not free of conflicting results. Accordingly, this study aimed to figure out if chronic consumption of morphine in the drinking water can induce morphine addiction in Wistar rats. METHODS: For 3 weeks, the animals received a daily morphine dose of 35 mg/kg by offering a calculated volume of sugar water (5% sucrose) with morphine (0.1 mg/ml) to each rat; animals receiving just sugar water served as controls. Immediately after the treatment phase, the tail immersion test was used to check for morphine tolerance, and all animals were then kept on tap water for one week (withdrawal phase). Afterwards, all rats were allowed to choose their drinking source by offering two bottles, containing sugar water without and with morphine, simultaneously for two days (preference phase). RESULTS: While the chronic consumption of morphine led to a reduction in body weight and to morphine tolerance, the morphine-treated Wistar rats did not show any preference for the opiate-containing sugar water. CONCLUSION: Body weight loss and tolerance do not reveal a condition of drug craving, and current animal models should be re-evaluated regarding their potential to establish morphine addicted animals.