Duck H. Suh

Effect of a chemical mixture on dermal penetration of arsenic and nickel in male pig in vitro

Abstract The effect of a chemical mixture on the dermal penetration of arsenic or nickel was assessed by applying arsenic-73 or nickel-63 alone or with the chemical mixture to dermatomed male pig skin samples in flow-through diffusion cells. The chemical mixture consisted of chloroform, phenanthrene, and toluene for arsenic penetration studies and phenol, toluene, and trichloroethylene (TCE) for nickel studies. These are predominant chemicals found at hazardous waste sites. Arsenic and nickel bind to skin after dermal exposure. Total penetration of arsenic and nickel in the chemical mixture were significantly increased by 33% and 20% compared to arsenic and nickel alone, respectively. While more radioactivity penetrated skin with chemical treatment than metal alone, significantly less radioactivity was loosely adsorbed to skin and could be easily washed off from the skin surface with soap and water. The results of this study indicate that the potential health risk from dermal exposure to arsenic or nickel is enhanced if other chemicals are present.

Mechanism of Chloroform Formation by Chlorine and Its Inhibition by Chlorine Dioxide

Chlorination of drinking waters leads to the formation of trihalomethanes arising from the reaction of chlorine and organic substances. Therefore, chlorine dioxide (ClO2) which does not produce trihalomethanes is being considered as an alternative disinfectant. It has been reported that rat blood chloroform levels were significantly decreased after treatment with ClO2. Studies were conducted to investigate the mechanisms of chloroform formation by chlorine (HOCl) and its inhibition by ClO2 (5 mg/liter) in the presence of HOCl (5, 10, 20 mg/liter) using sodium citrate (1 mM) as an organic substance. When citrate was reacted with HOCl, beta-ketoglutaric acid, monochloroacetone, dichloroacetone, and trichloroacetone were produced as reaction intermediates and chloroform as a final product. There was a linear relationship between the concentrations of HOCl and the formation of chloroform. When ClO2 was substituted for HOCl, neither chloroform was formed nor citrate concentration was changed. Further, chloroform formation was inhibited by ClO2 in the presence of HOCl and citrate and the degree of inhibition depends on the ratio of ClO2/HOCl. Gas chromatograph/mass spectrometer analysis indicates that this inhibition is related to the reaction of ClO2 with beta-ketoglutaric acid to form malonic acid. Chlorine dioxide also oxidizes other intermediates such as monochloroacetone and dichloroacetone to acetic acid. These studies indicate that ClO2 inhibits chloroform formation from citrate and HOCl by the oxidation of the intermediates which were involved in the reaction of chloroform formation.

Biochemical interactions of chlorine dioxide and its metabolites in rats

The problems arising from trihalomethanes formation resulting from the inadvertent reactivity of chlorine with organic compounds contained in water supplies suggest an alternative to chlorine may be desirable. Chlorine dioxide (ClO2), which does not form trihalomethanes, is being considered as a very attractive alternative disinfectant. The study was conducted to examine the effect of ClO2 and its metabolites on the formation of chloroform,3H-thymidine incorporation in organs, and hepatic microsomal enzyme activities in rats. Male rats were administered 0, 10, 100 mg/L ClO2 or 1, 10 mg/L of ClO2- or ClO3- daily for one year in the drinking water. Blood chloroform levels were significantly decreased in the ClO2 groups at 2, 10 and 12 months treatment. Chlorite and chlorate groups show similar decreases in blood chloroform concentration after one year. However, no significant chloroform values in liver, kidney, spleen, testes, and brain were observed in any treatment groups at the same time period. Chlorine dioxide (5 mg/L) inhibits the formation of chloroform by HOCl (5, 10, 20 mg/L) and sodium citrate (1 mM) and the degree of inhibition depends on the ratio of ClO2/ HOCl.ClO2 and ClO2- administered in drinking water for three weeks inhibited the incorporation of3H-thymidine into nuclei of rat testes and small intestine. The incorporation in the liver was increased in both 10 and 100 mg/L ClO2 groups. Hepatic enzyme assays revealed that aniline hydroxylase activity was significantly increased in the 100 mg/L ClO2 group and hexobarbital sleep time studies showed slight decreases in the ClO2 treatment groups after one year treatment.

Toxicity of monochloramine in rat: an alternative drinking water disinfectant

Monochloramine (NH2Cl) is under consideration as an alternative to chlorine as a disinfectant in public water supplies, to avoid trihalomethanes formation. This study was conducted to investigate the toxicity of NH2Cl (0, 1, 10, 100 mg/l) in drinking water. Glutathione (GSH) content in rat blood was decreased significantly after 4 mo treatment, and the decreases were consistent throughout the treatment period. Treatment groups showed a slight increase in blood osmotic fragility. After acute administration (3 ml) of 20 and 40 mg NH2Cl/l, blood GSH levels were increased as early as 15 min and the increases were consistent up to 1 h. After 2 h exposure, however, the GSH content returned to the control value. At 3 mo, red-blood-cell count and hematocrit were decreased significantly, while after 10 mo treatment significant decreases in hemoglobin concentration and mean corpuscular hemoglobin were observed. Monochloramine administered in drinking water for 3 mo increased the incorporation of [3H]thymidine into nuclei of rat kidney and spleen in the 1- and 10-mg/l groups, while the incorporation in testes was increased only in the 100-mg/l group. The body weight of rats was decreased significantly in the highest treatment group after 3 mo treatment, and the decrease persisted throughout the period studied. An examination of blood chloroform content in all the groups after 4, 6, 9, and 12 mo showed no significant changes compared to the control.

The Use of Kinetic and Dynamic Data in Risk Assessment of Drugs

The risk assessment process for non-carcinogens must incorporate all available scientific information, including toxicokinetic and toxicodynamic data. The framework for exposure limit setting proposed by Renwick and the International Programme on Chemical Safety (IPCS) subdivides traditional 10X uncertainty factors (UFs) into separate partial-log default values based on kinetic and dynamic considerations and allows for incorporation of compound-specific data when available. In this investigation, an extensive literature search was conducted on nine pharmaceuticals in order to incorporate information on kinetics and dynamics to allow extrapolation across species and among susceptible humans. The drugs are diazepam, oxazepam, midazolam, buspirone, fluoxetine, venlafaxine, amlodipine, felodipine, and nifedipine. The composite factors were calculated using the highest ratio or the average ratio for appropriate parameters and default subfactor. For the drugs examined, most of the subfactors for kinetics and dy...

Kinetics study of chloride in rat

The kinetics of chloride were studied in Sprague-Dawley rats following the oral administration of Na36Cl. The half-life for 36Cl- absorption from plasma was 19.2 h corresponding to a rate constant of 0.0361 h-1, while the half-life for 36Cl- elimination from plasma was 51.9 h, corresponding to a rate constant of 0.0134 h-1. At 120 h, radioactivity was highest in plasma, followed by kidney, lung, stomach, and spleen, and the lowest activity was observed in fat. Plasma and packed cells contained almost the same concentration of 36Cl-. Plasma protein binding of chloride was significantly higher than liver protein binding. Subcellular distribution in liver fractions revealed that most of the 36Cl- was located in the cytosolic fraction. The excretion of chloride occurred primarily by the kidney.

Evaluating the 10X Uncertainty Factor for Children and Elderly with Data-Derived Values for Neuromuscular Blocking Agents

Conventional risk assessment process utilizes a 10-fold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and elderly. The purpose of this investigation was to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharmacody-namic data are incorporated to characterize human sensitivity. An extensive literature search was conducted on seven neuromuscular blocking agents (mivacurium, atracurium, rocuronium, vecuronium, doxacurium, pancuronium, pipecuronium). Composite factors (kinetics × dynamics) were calculated using the highest data-derived kinetic and dynamic values. For the drugs examined, all of the composite factors for the sensitivity of children were lower than 5. In the elderly, all of the composite factors were lower than 10, and five of seven composite factors were less than 5. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce the uncertainties associated with sensitive subgroups.

Regular articleMechanism of chloroform formation by chlorine and its inhibition by chlorine dioxide

Chlorination of drinking waters leads to the formation of trihalomethanes arising from the reaction of chlorine and organic substances. Therefore, chlorine dioxide (ClO2) which does not produce trihalomethanes is being considered as an alternative disinfectant. It has been reported that rat blood chloroform levels were significantly decreased after treatment with ClO2. Studies were conducted to investigate the mechanisms of chloroform formation by chlorine (HOCl) and its inhibition by ClO2 (5 mg/liter) in the presence of HOCl (5, 10, 20 mg/liter) using sodium citrate (1 mM) as an organic substance. When citrate was reacted with HOCl, beta-ketoglutaric acid, monochloroacetone, dichloroacetone, and trichloroacetone were produced as reaction intermediates and chloroform as a final product. There was a linear relationship between the concentrations of HOCl and the formation of chloroform. When ClO2 was substituted for HOCl, neither chloroform was formed nor citrate concentration was changed. Further, chloroform formation was inhibited by ClO2 in the presence of HOCl and citrate and the degree of inhibition depends on the ratio of ClO2/HOCl. Gas chromatograph/mass spectrometer analysis indicates that this inhibition is related to the reaction of ClO2 with beta-ketoglutaric acid to form malonic acid. Chlorine dioxide also oxidizes other intermediates such as monochloroacetone and dichloroacetone to acetic acid. These studies indicate that ClO2 inhibits chloroform formation from citrate and HOCl by the oxidation of the intermediates which were involved in the reaction of chloroform formation.

Kinetic and dynamic data of analgesics and NSAIDs drugs reduce 10X uncertainty factors

Abstract The risk assessment process must use all available toxicological data and scientific evidence on the adverse effects of chemicals or drugs. The relationship between biological indicators and exposure or tissue burdens is determined by the pharmacokinetic and pharmacodynamic behavior of the chemical. The purpose of the present project was to investigate the use of pharmacokinetic and pharmacodynamic data in reducing the uncertainties in establishing exposure levels for some analgesics and non‐steroidal anti‐ inflammatory drugs (NSAIDs). Five pharmaceuticals were evaluated, namely: naproxen, acetaminophen, aspirin, ibuprofen and ketoprofen. The pharmacokinetic and pharmacodynamic parameters in inter‐ and intra‐species were evaluated. The composite factors for all the examined drugs were far less than 100. The present study indicated that the formation of data basis for different chemicals based on pharmacokinetic and pharmacodynamic behavior is important in setting up exposure levels, rather than t...

Assessing human health risks of chemicals and drugs: An overview

Abstract The risk assessment process for non‐carcinogens involves extrapolation of toxicological animal data to humans by applying uncertainty factors (UF). A 10‐fold UF is most commonly used to ac...