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Archives of Toxicology (v.84, #11)
Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples by Douglas B. Kell (pp. 825-889).
Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.
Keywords: Antioxidants; Apoptosis; Atherosclerosis; Cell death; Chelation; Chemical toxicology; Iron; Neurodegeneration; Phlebotomy; Polyphenols; Sepsis; SIRS; Stroke; Systems biology; Toxicity
Identification and distribution of mercury species in rat tissues following administration of thimerosal or methylmercury by Jairo L. Rodrigues; Juliana M. Serpeloni; Bruno L. Batista; Samuel S. Souza; Fernando Barbosa Jr (pp. 891-896).
Methylmercury (Met-Hg) is one the most toxic forms of Hg, with a considerable range of harmful effects on humans. Sodium ethyl mercury thiosalicylate, thimerosal (TM) is an ethylmercury (Et-Hg)-containing preservative that has been used in manufacturing vaccines in many countries. Whereas the behavior of Met-Hg in humans is relatively well known, that of ethylmercury (Et-Hg) is poorly understood. The present study describes the distribution of mercury as (-methyl, -ethyl and inorganic mercury) in rat tissues (brain, heart, kidney and liver) and blood following administration of TM or Met-Hg. Animals received one dose/day of Met-Hg or TM by gavage (0.5 mg Hg/kg). Blood samples were collected after 6, 12, 24, 48, 96 and 120 h of exposure. After 5 days, the animals were killed, and their tissues were collected. Total blood mercury (THg) levels were determined by ICP-MS, and methylmercury (Met-Hg), ethylmercury (Et-Hg) and inorganic mercury (Ino-Hg) levels were determined by speciation analysis with LC-ICP-MS. Mercury remains longer in the blood of rats treated with Met-Hg compared to that of TM-exposed rats. Moreover, after 48 h of the TM treatment, most of the Hg found in blood was inorganic. Of the total mercury found in the brain after TM exposure, 63% was in the form of Ino-Hg, with 13.5% as Et-Hg and 23.7% as Met-Hg. In general, mercury in tissues and blood following TM treatment was predominantly found as Ino-Hg, but a considerable amount of Et-Hg was also found in the liver and brain. Taken together, our data demonstrated that the toxicokinetics of TM is completely different from that of Met-Hg. Thus, Met-Hg is not an appropriate reference for assessing the risk from exposure to TM-derived Hg. It also adds new data for further studies in the evaluation of TM toxicity.
Keywords: Mercury; Distribution; Methylmercury; Ethylmercury; Inorganic mercury; Speciation analysis; Tissues; Toxicity; Thimerosal
Trichloroacetic acid in urine as biological exposure equivalent for low exposure concentrations of trichloroethene by György A. Csanády; Thomas Göen; Dominik Klein; Hans Drexler; Johannes G. Filser (pp. 897-902).
A urinary trichloroacetic acid (TCA) concentration of 100 mg/l at the end of the last work shift (8 h/day, 5 days/week) of the week has been established in workers as exposure equivalent for the carcinogenic substance trichloroethene (EKA for TRI) at an exposure concentration of 50 ppm TRI. Due to the continuous reduction of atmospheric TRI concentrations during the last years, the quantitative relation given by the EKA for TRI is revised for exposures to low TRI concentrations. A physiological two-compartment model is presented by which the urinary TCA concentrations are calculated that result from inhaled TRI in humans. The model contains one compartment for trichloroethanol (TCE) and one for TCA. Inhaled TRI is metabolized to TCA and to TCE. The latter is in part further oxidized to TCA. Urinary elimination of TCA is modeled to obey first order kinetics. All required model parameters were taken form the literature. In order to evaluate the model performance on the urinary TCA excretion at low exposure concentrations, predicted urinary TCA concentrations were compared with data obtained in two volunteer studies and in one field study. The model was evaluated at exposure concentrations as low as 12.5 ppm TRI. It is demonstrated that the correlation described by the hitherto used EKA for TRI is also valid at low TRI concentrations. For TRI exposure concentrations of 0.6 and 6 ppm, the resulting urinary TCA concentrations at the end of the last work shift of a week are predicted to be 1.2 and 12 mg/l, respectively.
Keywords: Trichloroethene; Trichloroacetic acid; Trichloroethanol; Occupational exposure; Inhalation; Urine