Derivation of internal dose-based thresholds of toxicological concern for occupational inhalation exposure to systemically acting organic chemicals

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61?×?10^?2 and 9?×?10^?4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55?×?10^?1 and 8.5?×?10^?3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r² = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework.     

Morphological and biochemical correlates of chemical induced injury in the lung

We have reviewed some of the factors which contribute to lung damage by various toxicants. These include disposition of the chemical, its metabolism, individual cell type susceptibility and the potential for the tissue to repair. We have discussed the use of biochemical parameters to measure the functional activity of individual cell types in order to predict the damage to specific cell types and concluded that careful morphological analysis of lung tissue is likely to provide a more sensitive and informative measure of specific cell type injury. However, in order to investigate the mechanism of toxicity of pulmonary toxicants it is essential to establish the primary biochemical event that leads to cell damage and morphological change. The importance of separating the relevant biochemical change(s) from the cascade of biochemical events associated with dead and dying cells and the reparative response of the lung is emphasised.This report results from a discussion sponsored and organised by the Advisory Subgroup in Toxicology (AST) of the European Science Foundation's Standing Committee for the European Medical Research Councils and held at the Medical Research Council Toxicology Unit, Carshalton, U. K. Those taking part were: W. N. Aldridge (AST; as above); J. Bignon (Unit for Research in Renal and Pulmonary Pathology, University of Paris, Creteil, France); P. H. Burri (Section of Developmental Biology, Institute of Anatomy, University of Berne, Switzerland); G. M. Cohen (as above); D. Dinsdale (MRC Toxicology Unit, Carshalton U. K.); P. Hedqvist (Dept. of Physiology, Karolinska Institute, Stockholm, Sweden); D. Henschler (AST; Dept. of Toxicology and Pharmacology, University of Wurzburg, FDR); G. J. Laurent (Biochemistry Unit, Cardiothoracic Institute, University of London, London, U. K.); R. Lauwerys (AST Industrial and Medical Toxicology Unit, University of Louvain, Brussels, Belgium); F. Lembeck (AST; Dept. for Experimental and Clinical Pharmacology, University of Graz, Austria); N. Lery (AST; Poison Control Centre, Lyon, France); P. Moldeus (Dept. of Forensic Medicine, Karolinska Institute, Stockholm, Sweden); B. Nemery (MRC Toxicology Unit, Carshalton, U. K.); A. Saria (Dept. for Experimental and Clinical Pharmacology, University of Graz, Austria); L. L. Smith (as above);B. Terracini (AST; Dept. of Pathology and Cancer Epidemiology, University of Turin, Italy)     

Characteristic modifications of the breathing pattern of mice to evaluate the effects of airborne chemicals on the respiratory tract

A system was developed for exposure of unanesthetized mice to airborne chemicals and for continuous measurement of their breathing pattern prior to, during and following exposure. By measuring inspiratory and expiratory airflows (VI and VE), and integration with time to yield tidal volume (VT), we obtained characteristic modifications to the normal breathing pattern. These permitted recognition that a specific portion of the respiratory tract was affected by the selected airborne chemicals. Following recognition, we also quantitated the degree of effect using one specific measurement in each case. An effect on the upper respiratory tract, induced by the sensory irritant, 2-chlorobenzylchloride, was quantitated by measuring a decrease in respiratory frequency. An effect on the conducting airways, induced by the airway constrictor, carbamylcholine, was quantitated by a decrease in VE at the mid-point of VT. An effect at the alveolar level, induced either by the vagal nerve ending stimulant, propranolol, or by the pulmonary irritant, machining fluid G, was quantitated by an increase in the length of a pause induced at the end of expiration. The system is easy to construct and operate and can be used to rapidly evaluate the effects of airborne chemicals on the respiratory tract.     

Studies on capsaicin inhibition of chemically induced lipid peroxidation in the lung and liver tissues of rat

Previous work from this laboratory has already indicated that capsaicin, stabilizes the rat lung membrane lipid system on long-term treatment. This stabilization of the membrane is further supported by our present findings that capsaicin pretreatment causes significant inhibition of various chemically induced lipid peroxidative changes at both cellular and subcellular levels. Both in vivo and in vitro studies, using whole lung and liver tissue slices and mitochondrial and microsomal fractions, have shown that capsaicin pretreatment inhibits peroxidative changes at both cellular and subcellular levels. Both in vivo and in vitro studies, using whole lung and liver tissue slices and mitochondrial and microsomal fractions, have shown that capsaicin pretreatment inhibits peroxidative changes induced by different chemical irritants such as chloroform, dichloromethane, carbon tetrachloride as well as ferrous sulphate.     

Testing for skin sensitization according to the notification procedure for new chemicals: the Magnusson and Kligman test

The notification procedure for new chemicals in the European Union (called the Chemicals Act in Germany) requires a skin sensitization test when the amount of a new chemical produced exceeds 100 kg/year. The preferred test is that of Magnusson and Kligman; more than 90% of the tests submitted are performed with it. Though the Magnusson and Kligman test is described in the literature, and in the test guidelines of the European Union and of the OECD, discrepancies do occur in the performance of the test between test laboratories. In this paper, recommendations are given for standardized performance of the Magnusson and Kligman test.     

Memory impairment associated with a dysfunction of the hippocampal cholinergic system induced by prenatal and neonatal exposures to bisphenol-A

One of the most common chemicals that behaves as an endocrine disruptor is the compound 4,4′-isopronylidenediphenol, called bisphenol-A. In the previous study, we reported that exposure to bisphenol-A induced the abnormality of dopamine receptor functions in the mouse limbic area, resulting in a supersensitivity of drugs of abuse-induced pharmacological actions. The present study was undertaken to investigate whether prenatal and neonatal exposures to bisphenol-A could alter other behavioral abnormalities such as anxiogenic behavior, motor learning behavior, or memory. In the present study, adult female mice were chronically treated with bisphenol-A-admixed powder food from mating to weaning. All experiments were performed using male pups. Here we found that prenatal and neonatal exposures to bisphenol-A failed to induce anxiogenic effects and motor-learning impairment using the light-dark test, elevated plus maze test, and rota-rod test. On the other hand, we found that prenatal and neonatal exposures to bisphenol-A induced the memory impairment using the step-through passive avoidance test. Immunohistochemical study showed the dramatic reduction in choline acetyltransferase-like immunoreactivity, which is a marker of acetylcholine (ACh) production, in the hippocampus of mice prenatally and neonatally exposed to bisphenol-A. These results suggest that chronic exposures to bisphenol-A could induce the memory impairment associated with the reduction in ACh production in the hippocampus.     

环境化学物暴露对2型糖尿病基因的富集进程和通路影响研究

目的 探讨2型糖尿病（T2DM）共同差异表达基因的富集进程和通路，并进一步发现影响T2DM的环境化学物质。方法 通过比较毒理基因组学数据库（CTD）中获取直接作用的T2DM相关基因及化学物质，从GEO数据库中获取T2DM关联的基因。对T2DM关联的共同关键基因进行富集分析，获取共同基因/蛋白可能参与的生物进程或信号通路。结果 共有469个与T2DM关联的基因，200个关键基因/蛋白富集发现，这些关键基因/蛋白参与了MAPK级联正调控、细胞因子介导的信号通路、ER到高尔基体的顺行转运、细胞外刺激应答等信号通路。结论 环境化学物质能在基因水平上影响T2DM的发生发展。     

Economic burden of acute pesticide poisoning in South Korea

Objectives To investigate the magnitude and characteristics of the economic burden resulting from acute pesticide poisoning (APP) in South Korea. Methods The total costs of APP from a societal perspective were estimated by summing the direct medical and non‐medical costs together with the indirect costs. Direct medical costs for patients assigned a disease code of pesticide poisoning were extracted from the Korean National Health Insurance Reimbursement Data. Direct non‐medical costs were estimated using the average transportation and caregiving costs from the Korea Health Panel Survey. Indirect costs, incurred by pre‐mature deaths and work loss, were obtained using 2009 Life Tables for Korea and other relevant literature. Results In 2009, a total of 11 453 patients were treated for APP and 1311 died, corresponding to an incidence of 23.1 per 100 000 population and a mortality rate of 2.6 per 100 000 population in South Korea. The total costs of APP were estimated at approximately US$ 150 million, 0.3% of the costs of total diseases. Costs due to pre‐mature mortality accounted for 90.6% of the total costs, whereas the contribution of direct medical costs was relatively small. Conclusion Costs from APP demonstrate a unique characteristic of a large proportion of the indirect costs originating from pre‐mature mortality. This finding suggests policy implications for restrictions on lethal pesticides and safe storage to reduce fatality and cost due to APP.     

Intoxications of the new psychoactive substance 5-(2-aminopropyl)indole (5-IT): A case series from the Swedish STRIDA project

Context. 5-(2-aminopropyl)indole (5-IT) is a new psychoactive substance (NPS; “legal high” or “research chemical”) structurally related to indoleamines and substituted phenethylamines and implicated in several fatalities. We describe the clinical characteristics and results of laboratory investigations of 14 analytically confirmed nonfatal cases of 5-IT intoxication within the Swedish STRIDA project. Study design. Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden in 2012. Patients and methods. Blood and/or urine samples were collected from intoxicated patients presenting to emergency departments and intensive care units over the country. Analysis of NPS was performed using an LC–MS/MS multi-component method. Clinical data were collected when caregivers consulted the Poisons Information Centre and also retrieved from medical records. The severity of poisoning was graded retrospectively using the Poisoning Severity Score (PSS). Results. Eleven male and three female patients (age: 21–53 years, median: 27) tested positive for 5-IT in 2012, all cases appearing in April–July. The 5-IT concentration in serum ranged between 0.015 and 0.59 μg/mL (median: 0.22; n = 8) and in urine between 0.005 and 24.7 μg/mL (median: 5.95; n = 12). Five intoxications were indicated to be caused by 5-IT alone, whereas additional psychoactive substances were detected in the other nine cases. Six (43%) of fourteen cases were graded as severe (PSS 3), five (36%) as moderate (PSS 2), and three (21%) as minor (PSS 1) poisonings. In the severe cases, agitation, hallucinations, dilated pupils without light reaction, tachycardia, hypertension, hyperthermia, myoclonus, muscle rigidity, arrhythmias, seizures, rhabdomyolysis, and/or renal failure were noted. Conclusions. The results demonstrated that severe clinical toxicity was commonly present in patients with analytically confirmed 5-IT exposure. The clinical features are consistent with a sympathomimetic toxidrome, and some patients also displayed symptoms associated with serotonin toxicity.     

Endocrine-Disrupting Chemicals: Prepubertal Exposures and Effects on Sexual Maturation and Thyroid Activity in the Female Rat. A Focus on the EDSTAC Recommendations

In 1996, the US Environmental Protection Agency was given a mandate by Congress to develop a screening program that would evaluate whether variously identified compounds could affect human health by mimicking or interfering with normal endocrine regulatory functions. Toward this end, the Agency chartered the Endocrine Disruptor Screening and Testing Advisory Committee in October of that year that would serve to recommend a series of in vitro and in vivo protocols designed to provide a comprehensive assessment of a chemical's potential endocrine-disrupting activity. A number of these protocols have undergone subsequent modification by EPA, and this review focuses specifically on the revised in vivo screening procedure recommended under the title Research Protocol for Assessment of Pubertal Development and Thyroid Function in Juvenile Female Rats. Background literature has been provided that summarizes what is currently known about pubertal development in the female rat and the influence of various forms of pharmaceutical and toxicological insult on this process and on thyroid activity. Finally, a section is included that discusses technical issues that should be considered if the specified pubertal endpoints are to be measured and successfully evaluated.