Оценка риска для здоровья, связанного с применением репеллентов на основе N,N--диэтил-м-толуамида (ДЭТА)

Conventional health risk assessments do not adequately reflect short-term exposure characteristics following chemical accidents. We aimed to evaluate the efficacy of existing assessment methods and propose a more suitable risk assessment approach for short-term exposure to hazardous chemicals. We analyzed foundational studies used to derive reference concentration (RfC), reference dose (RfD), and minimal risk level (MRL) values and applied these health guidance values (HGVs) to a hypothetical chemical accident scenario. An analysis of the studies underlying each HGV revealed that, except for the RfC for formaldehyde and the RfD for toluene, all values were derived under research conditions comparable to their respective exposure durations. Given the differing toxicity mechanisms between acute and chronic exposures, MRLs that were aligned with the corresponding exposure durations supported more appropriate risk management decisions. The health risk assessment results showed that RfC/RfD-based hazard quotients (HQs) were consistently higher than MRL-based HQs across all age groups and both substances, indicating that RfC/RfD values tend to yield more conservative risk estimates. For formaldehyde, the use of RfC instead of MRL resulted in an additional 208 tiles (2.08 km2) being classified as areas of potential concern (HQ > 1) relative to the MRL-based evaluation. These findings highlighted that the selection of HGVs can significantly influence the spatial extent of areas of potential concern, potentially altering health risk determinations for large population groups. This study provides a scientific basis for improving exposure and risk assessment frameworks under short-term exposure conditions. It also serves as valuable foundational data for developing effective and rational risk management strategies during actual chemical accidents. To the best of our knowledge, this is the first study to apply MRLs to a short-term chemical accident scenario and directly compare them with traditional reference values.

Dimethylcyclosiloxanes (DMCS) are components of silicone gel containing implants and are known inducers of human drug metabolizing enzymes. The effects of the major DMCS, octamethyltetracyclosiloxane (D4) on cytochrome P450 (CYP) induction were examined in young adult, mature, and pregnant female Sprague-Dawley rats. Also, the ability of D4 administered to pregnant dams to affect CYP expression in fetal liver was examined. Female young, mature, and pregnant Sprague-Dawley rats were administered 0, 5, 20, and 100 mg/kg D4 daily by gavage for 8 days. Liver microsomal CYP (CYP2B, CYP3A, CYP1A) concentrations were evaluated by Western blots using specific antisera, and CYP activities were assayed using CYP selective assays. D4 treatment resulted in a significant induction of CYP2B and CYP3A isoforms. CYP induction was dose and age dependent. A comparison of the inducibility of CYP3A protein by D4 in rats from different age groups showed that the degree of increase was the highest in the pregnant rats at doses of 20 mg/kg D4 or higher. The mature rats had a lesser degree of responsiveness than did the young rats at the dose of 100 mg/ kg D4. Significant increases in CYP2B immunoreactive protein concentrations were observed in young and mature rats given D4 at doses >5 mg/kg and in pregnant rats at doses >20 mg/kg. Maximal CYP2B induction detected with blotting was more than 90-fold in mature rats; however, no significant changes were detected in CYP1A expression. There was a 20% increase of liver to body weight ratio in the mature rats treated with 100 mg/kg D4. D4 has different inductive properties in female rats of different ages and reproductive status. Also, D4 administered to the pregnant dam is capable of inducing CYP expression in fetal liver as well as decreasing fetal body weight.

The purpose of this study was to compare the febrile responses of Fischer 344 rats of different ages [young (3-5 mo), mature (12-15 mo), and aged (24-27 mo; n = 8)] to two psychological stress paradigms, cage switch and exposure to an open field, as well as to injection of lipopolysaccharide (LPS). In addition, the cytokines tumor necrosis factor-alpha (TNF) and interleukin-6 were also measured in the plasma of these rats at 90 min postinjection with LPS. There was no significant difference among groups in febrile responses to switching their cages. Exposure to an open field for 30 min resulted in a smaller rise in temperature in the aged rats (0.62 degree C) than in the young rats (1.26 degrees C). This difference disappeared if rats were exposed to an open field for 60 min. Injection of LPS led to fevers that developed at a slower rate in aged rats than in the mature groups. The peak fevers, however, were not different. The activity of interleukin-6 90 min after injection of LPS was higher in aged rats (297,858 U/ml) than in young (17,462 U/ml) and mature rats (28,819 U/ml). TNF levels were also higher in aged rats (16,380 U/ml) compared with young (574 U/ml) and mature rats (36 U/ml). We conclude that although the magnitude of the febrile response is not different among rats of different ages, the rise in body temperature occurs slower in aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of a site-specific reference dose for methylmercury for fish-eating populations.

Authors' response.

A Two-stage Simulation Assisted Differential Evolution Algorithm for Reliable Chance Constrained Programming with Minimum Risk Level

Метою дослідження було визначення рівня мелатоніну в сироватці крові у щурів різної статі та віку при виразковому ураженні шлунка. Матеріали та методи. Методом спирто-преднізолонового ушкодження моделювали виразкове ураження шлунка та за допомогою імуноферментного аналізу визначали рівні мелатоніну в сироватці крові у щурів різної статі, які були розподілені на групи за віком, а саме — 3, 9, 15 та 20 міс., що відповідає віку людини 14, 29–30, 43–44, 55–56 років відповідно. Результати. Встановлено, що на тлі виразкового ураження шлунка відбувається вірогідне зниження рівня мелатоніну як у самців, так і у самок у всіх вікових групах. Відносно групи контролю у щурів-самців найбільше зниження відбулося у тварин віком 9 та 20 міс. — на 39 та 43 % відповідно (р ≤ 0,05). У самок на тлі виразкового ураження шлунка зниження рівня мелатоніну відносно групи контролю було на 21–23 % (р ≤ 0,05). Обговорення. Отримані результати свідчать, що виразкове ураження шлунка, ймовірно, призводить до пошкодження ентерохромафінних клітин слизової оболонки шлунка, що супроводжується вірогідними зниженнями рівнів мелатоніну у щурів обох статей і всіх вікових груп, та дозволяють припустити, що саме у чоловіків віком 29–30 та 55–56 років виразкове ураження призводить до значного пошкодження екстрапінеальних джерел синтезу мелатоніну та більш тяжкого перебігу виразкової хвороби з розвитком ускладнень. Висновки. Таким чином, виразкове ураження шлунка призводить до зниження рівнів мелатоніну в сироватці крові у щурів різної статі та віку. Найбільше зниження рівнів мелатоніну при експериментальній виразці шлунка відбувається у щурів-самців віком 9 та 20 міс., що відповідає віку людини 29–30 та 55–56 років.

Selective reduction of hippocampal dentate frequency potentiation in aged rats with impaired place learning

An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 microgram/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 microgram/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 microgram/kg/day and an MRL of 0.3 microgram/kg/day.

Differential changes of cAMP-dependent protein kinase activity and 3H-cAMP binding sites in rat hippocampus during maturation and aging

Introduction. In the modern urbanized society, people of all age groups are at high risk of suffering from combined cranio-skeletal trauma (CST). Oxidative stress plays a key role in the pathogenesis of CST. Reduced glutathione (GSH) is one of the antioxidants that prevents the formation of free radicals. In order to prevent secondary damage to the brain and internal organs in the case of trauma, the effect of cell therapy is being actively studied. The aim of the study. To determine the age-related peculiarities of glutathione antioxidant system dynamics in response to cranio-skeletal trauma and to evaluate the effectiveness of cell therapy. Materials and methods. Male white Wistar line rats of three age groups were used in the experiments: immature, mature, and old. The rats of each age group were modeled with CST. After 1, 3, 7, 14, 21 and 28 days, the content of GSH was determined in the liver homogenate extract. For the purpose of correction, a suspension of cryopreserved neuroblast cells (NBC) was intravenously injected individually and in combination with intraperitoneal injection of mesenchymal stem cells (MSC). The effectiveness of the therapy was evaluated after 14 days of experiment. Results. Among rats of different ages under conditions of CST, compared with the control, the content of GSH in the liver significantly decreased at all studied periods of the post-traumatic period. After 3, 14, 21, and 28 days of the post-traumatic period, with increasing age, the absolute value of the index became statistically significantly lower and the degree of its decrease increased. The use of NBC monotherapy in comparison with rats without correction was accompanied by the protection of GSH content in the liver of immature and mature rats. Combined NBC+MSC therapy was accompanied by a similar effect among rats of all age groups. Both after NBC monotherapy and combination therapy, the degree of increase in the liver GSH content was significantly higher among mature rats compared to immature and old rats. Conclusions. Experimental cranio-skeletal trauma among rats of different ages compared to controls leads to a decrease in the content of reduced glutathione in the liver, which significantly prevails among old rats. The combined use of cryopreserved neuroblast cells and mesenchymal stem cells in the case of cranio-skeletal trauma is accompanied by significantly higher deposition of reduced glutathione in the liver among rats of all age groups. The degree of increase in the index prevails in the group of mature rats compared to rats without correction.

In male rats of different ages, we studied the functional activity of the pineal gland and the gonads during different seasons by determining the levels of melatonin and testosterone in the blood serum. It was found that the highest levels of melatonin observed in male rats in summer and winter, and the lowest - in autumn. The lowest level of melatonin has been established in the group of rats aged 9 months - 127.28+5.11 pmol/l that was 22% lower than the level of melatonin in 3 months old rats (P!0,05), and 20% below the level of melatonin in rats of 15 months old (Ps0,05). The highest level determined in rats aged 3 months (corresponds to the age of man -14 years old), the lowest - in rats 20 months-(corresponds to the age 55-56 years old). At the same time, the low level of melatonin was defined in rats aged 9 months in the autumn (corresponds to the age of man 29-30 years). In the study of testosterone levels in different seasons it was found that the highest level in all age groups presents in autumn, the lowest - in winter. When comparing the levels of testosterone in different age groups, it was determined that the fall of the highest level of testosterone present in the blood of males age 9 months and 15 months, which corresponds to the age of 29-30 and 43-44 of human years. Significant difference between the levels of testosterone in the groups that correspond to the reproductive age - rats of age 3, 9 and 15 months, are present only in the autumn; spring and summer - significant differences between the levels of testosterone absent. The degree of correlation differed in rats of different ages in different seasons: the highest correlation between the levels of melatonin and testosterone was determined in rats aged 9 months in autumn. The correlation coefficients in rats aged 20 months old have been weak - from 0.05 in the spring to 0.17 in autumn that shows the changes in neurohormonal regulation which occur with age.

The annual increase in the number of older people in the world leads to the fact that diseases associated with human aging are becoming increasingly relevant. Existing and new data indicate a significant role of the GABA-ergic system in the mechanisms of Alzheimer's disease. In particular, it is known that the use of GABA-ergic compounds is associated with improved cognition. Some of the nootropics counteract the neurotoxicity of β-amyloid through the activation of GABA-ergic neurotransmission and themselves exhibit anti-amyloidogenic effects, which leads to a decrease in its deposition. Nevertheless, there are still many unclear questions, the answers to which could contribute to the prevention and treatment of the pathology.Objective of the work was to study the effect of carbacetam, as a modulator of GABA receptors, on behavioral response of rats of different ages with scopolamine induced Alzheimer’s disease.Material and methods. The experiments were conducted on nonlinear albino mature and old male rats. Alzheimer’s disease was simulated by scopolamine hydrochloride (Sigma, USA) introduced intraperitoneally (i/p) in the dose of 1 mg/kg of the body weight once a day for 27 days. On the 28th day, carbacetam was introduced intraperitoneally at a dose of 5 mg/kg once a day during 14 days. The functional state of the central nervous system was assessed by the behavioral response of rats in “open field” and conditioned passive avoidance reflex (CPAR) tests. The results were processed statistically by means of the t-Student criterion. The differences were considered statistically confident with р≤0,05.Results. Based on our research, we established that carbacetam positively changes indicators of motor, orientation-learning activity, emotional reactions and vegetative behavior in rats with Alzheimer’s disease. An increased latent period of entrance into the dark block after the introduction of carbacetam reflects effective maintenance of the conditioned passive avoidance reflex to electric painful stimulation. It demonstrates the improvement of cognitive function of rats of different ages with Alzheimer’s disease promoted by the new endogenic modulator of the GABA-ergic system.Conclusion. Modulation of GABA receptors with carbacetam confirms the suggestion concerning their role in the mechanisms of adaptation, learning activity and memory in rats of different age with experimental Alzheimer’s disease.

The Agency for Toxic Substances and Disease Registry (ATSDR) lists cadmium as one of its priority hazardous substances. The agency conducted a comprehensive literature review of cadmium and used the information to develop a toxicological profile that identified the full range of health effects associated with exposure to cadmium. It included an assessment that identified screening levels, termed health guidance values or minimal risk levels (MRLs), below which adverse health effects are not expected. In this paper, we describe how MRLs for cadmium are derived. For the acute inhalation MRL, the traditional no observed adverse effect level or lowest observed adverse effect level (NOAEL/LOAEL) approach is used; for the oral intermediate MRL, the benchmark dose (BMD) approach is used. MRLs were developed for the most sensitive route-specific end points, other than mortality and cancer that were sufficiently supported and justified by the data. These included an acute duration (1-14 day exposure) inhalation MRL of 0.03 µg Cd/m3 for alveolar histiocytic infiltration and focal inflammation in alveolar septa and an intermediate duration (15-365 day exposure) oral MRL of 0.5 µg Cd/kg/day for decreased bone mineral density.

The aim: To determine the peculiarities of the antioxidant-prooxidant balance in the kidney of rats of different ages under conditions of experimental cranioskeletal trauma (CST). Materials and methods: The experiments involved 147 male white Wistar rats of different age groups. The first experimental group included immature animals aged 100-120 days. The second group included sexually mature animals aged 6-8 months. The third group included old animals aged 19-23 months. In all experimental groups, CST was modelled under thiopental-sodium anaesthesia. The control groups of rats was only injected with thiopental-sodium anaesthesia. The animals were withdrawn from the experiments under anaesthesia after 1, 3, 7, 14, 21 and 28 days by total bleeding from the heart. The content of reagents to thiobarbituric acid and catalase activity was determined in a 10 % kidney homogenate extract, and the antioxidant-prooxidant index (API) was calculated from the ratio of these two parameters. Results: As a result of the application of CST in rats of different age groups, a decrease in the value of renal API was observed with a maximum in immature rats - after 7 days, in mature and old rats - after 14 days. By day 28, the index increased in all experimental groups, but did not reach the control level. The degree of decrease in renal API in old rats under the influence of CCT was significantly higher than in other experimental groups. In immature rats, the impairment of renal API after the application of CST was less, indicating higher reserve capacity of the renal antioxidant defence system in this age group of rats. Conclusions: Simulation of CST in rats of different age groups is accompanied by a decrease in the value of API, which by day 28 does not reach the control level in any of the experimental groups. The degree of decrease in renal API value statistically significantly increases with increasing age of rats at all times of the post-traumatic period.