Human & Experimental Toxicology

The number of definite and probable human chemical carcinogens identified by IARC approaches between 1987 and June 2004 is reported to be 50 agents. However, overall, given the rapid expansion in the number of chemicals in use, the throughput of the current approach to identifying potential environmental carcinogens is low. The long-term rodent bioassay, a key part of the current approach, identifies many chemicals which eventually turn out to be irrelevant for human health with regard to cancer. A new approach is suggested which focuses on identifying the potency of environmental mixtures for induction of toxicological changes relevant to carcinogenesis (e.g., cell proliferation, chronic inflammation, inhibition of apoptosis, mutagenicity). Details regarding a suggested strategy for prioritization of mixtures are provided with more detailed information regarding mutagenicity as an end point. The long-term rodent bioassay is not included in the proposal (although it is acknowledged that it will continue to be important in premarketing regulatory schemes) for hazard identification. The Multiple Chemicals and Actions Model (MCAM) is developed. In this model the chemical mixtures in the environment act via a number of mechanisms as ‘effectors’ or ‘inhibitors’ of a multistage carcinogenic process. Identifying effectors and inhibitors of the rate-limiting step would be important for preventive strategies. Genetic polymorphisms act as modulators of effector and inhibitor mixtures. It is suggested that the MCAM model could be used in public education programmes to help inform on public health issues regarding cancer and to help avoid future scares which tend to focus on single chemicals. It is acknowledged that there would need to be basic research undertaken to generate appropriate data to support the application of the proposal before it could be used in cancer prevention strategies.

Although liver injury is a recognized consequence of acute iron poisoning, its description is limited to several case reports. It appears to be dose-related, however, there are published reports of severe iron poisoning without liver injury. The purpose of this study is to examine the hypothesis that this is a dose-related phenomenon and to identify the serum iron concentration of risk for this outcome. The design of this study is a retrospective review of our hospital's experience over 20 years. Extracted data included demographics, time of ingestion, highest serum iron concentration and highest hepatic transaminase activity. Iron poisoning was defined as a serum iron concentration / 300 mg/dL (55 mmol/L) within 12 hours of ingestion. Hepatotoxicity was defined as a serum transaminase (either ALT or AST) / 150 U/L. Severe hepatotoxicity was defined as / 1000 U/L. Seventy-three patients (1 ^/ 704 mg/dL (55 ^/ 48 years old) participated in the study and of these patients 60 (47 female) did not have hepatotoxicity. Their serum iron concentrations were 300 ^/ 128 mmol/L). Thirteen patients had hepatotoxicity and of these patients, nine had severe liver injury. Severe injury was associated with serum iron concentrations well in excess of 1000 mg/dL (182 mmol/L). Our data support hepatotoxicity due to iron poisoning as a doserelated phenomenon with clinically important cases unlikely with a serum iron concentration of B / 700 mg/dL (128 mmol/L) within the first 12 hours. Clinically important hepatotoxicity occurs with values in excess of 1000 mg/dL (182 mmol/L).

Nutmeg is a spice that contains volatile oils comprised of alkyl benzene derivatives (myristicin, elemicin, safrole, etc.), terpenes and myristic acid. Nutmeg has a long history of abuse. This study describes the nutmeg ingestion calls received by Texas poison centers from 1998 to 2004. There were 17 calls involving nutmeg ingestion, of which 64.7% involved intentional abuse. When abuse and non-abuse ingestions were compared, abuse ingestions were more likely to involve males (100 versus 66.7%) and adolescents (55.6 versus 16.7%). The majority of both abuse and non-abuse calls were managed outside of health care facilities (54.5 and 66.7%, respectively). None of the ingestions resulted in more than moderate clinical effects or death.

The aims of our study were to assess whether the increased oxidative stress in experimental otitis media with effusion (OME) induced by histamine was reflected in erythrocytes and middle ear effusion fluid by lipid peroxidation; to survey the alterations in antioxidant enzyme activities in experimental OME; and to determine the effect of dantrolene on this oxidative stress. Erythrocyte and middle ear effusion malondialdehyde (MDA) level, erythrocyte glutathione (GSH) and glutathione peroxidase (GSH-Px), glutathione reductase (GRD) and glutathione-S-transferase (GST) activities were measured in three groups of seven guinea pigs, 3 hours after injection of 0.1 mL of histamine (or saline) into the middle ear in guinea pigs with OME (experimental group), in a dantrolene sodium group and in a control group.

Erythrocyte and effusion MDA levels in the dantrolene group were significantly lower than those of the experimental group. Erythrocyte GSH-Px, GST, GRD activities, and GSH levels were significantly higher in the dantrolene group than in the experimental group. Dantrolene sodium decreased the erythrocyte and effusion MDA levels, on the other hand, it increased the GSH and GSH-dependent enzymes.

These findings suggest that reactive oxygen species (ROS) play a role in histamine-induced OME. Pretreatment with dantrolene sodium increases antioxidant enzymes activities and decreases formation of MDA, the indicator of lipid peroxidation, in histamine induced OME.

Although Hoechst 33342 (H342) is frequently used to label donor cells in cell transplantation research, it has been noted that it might secondarily label the host cells. Furthermore, its potential toxicity leading to cell death has been described.

We studied the time course of H342 redistribution from the primary labeled rat bone marrow stromal cells (rBMSC) into the non-labeled rBMSC population over 7 days in culture; we evaluated the nuclear H342 fluorescence intensity as a possible criterion for distinguishing the primary from the secondary labeled cells, and determined the viability of rBMSC after an overnight incubation in 1 mg/mL of H342.

H342 labeled / 50% of the initially non-labeled cells within the first 6 hours and almost 90% within a week.Nuclear fluorescence intensity was a reliable criterion for distinguishing primary and secondary labeled cells within the first 24 hours, but less so at later time points. The percentage of either apoptotic or necrotic cells did not rise acutely after the overnight incubation in 1 mg/mL of H342.

Although a 12-hour incubation of rBMSC in 1 mg/mL of H342 did not cause acute cell death, H342 rapidly and extensively redistributed into non-labeled cells, which makes H342 a relatively unsuitable marker for cell transplantation research.

Recently, pyridoxal 2-chlorobenzoyl hydrazone (o-108) has been identified as an effective iron chelator [Link et al., Blood 2003; 101: 4172–79]. Since chronic treatment would be necessary in its potential indications, in the present study, the safety and tolerability of this agent after repeated administration was determined. Three doses of o-108 (25, 50, 100 mg/kg, in 10% Cremophor EL) were administered intraperitoneally, once weekly, for 10 weeks to three groups (n–5 each) of Chinchilla male rabbits. The effects on biochemical, haematological and cardiovascular parameters were examined during the experiment; histopathological examination was performed at the end of the experiment. Results were compared with control (saline 2 mL/kg, n–11) and vehicle groups (10% Cremophor EL, 2 mL/kg, n–12). No premature deaths occurred; the well-being of animals was evidenced by their body weight gain, although lower gain was observed with the highest dose (100 mg/kg). Significant elevations of cardiac troponin T plasma concentrations were observed with the highest dose of o-108, but no abnormalities were found in the cardiovascular function and only minor and inconsistent changes in haematological and biochemical parameters were observed. Histopathological examinations of selected organs revealed only weak and reversible changes through all studied groups. Thus, the data from this study suggest that o-108 remains a promising drug from the standpoint of the possibility of its repeated administration and warrants further investigation.

Published literature on the toxicity of a topiramate overdose is limited to case reports. This retrospective study of poison center data was performed to examine the severity of topiramate overdoses. Data on single substance exposures to topiramate reported to the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) in 2000 and 2001 were retrospectively analysed. A total of 567 cases met the inclusion criteria, of which 39% occurred in adults over 19 years of age and 30.2% in children 5 / 4 years old. The majority of patients (62.1%) experienced no toxicity. The most common clinical effects reported were drowsiness/lethargy (15.5%), dizziness/vertigo (4.9%), agitation (4.9%), confusion (3.9%), nausea (2.6%) and vomiting (2.5%). Symptomatic patients were older than asymptomatic patients and adults were more likely to be managed in a healthcare facility (P B / 0.0001). Patients who received gastrointestinal decontamination experienced less serious outcomes than those without decontamination (P B / 0.02). It is concluded that clinicians should expect relatively mild mental status changes in adults or children with toxicity from topiramate overdose. Serious toxic effects, such as CNS depression with respiratory depression or persistent non-anion gap metabolic acidosis, are infrequent.

Health professionals exposed to anesthetic gases are at higher risk of reproductive, neurological, hematological, immunological, hepatic and renal system diseases. We investigated if oxidative stress induced by chronic exposure to anesthetic gases has any association with this matter. Plasma lipid peroxidation, total antioxidant capacity and total thiol molecule levels were measured in 66 operating room staff in comparison with 66 controls. The exposed group had a significantly higher level of lipid peroxidation with decreased thiol groups compared to control subjects. Total antioxidant capacity of the body was no different among exposed and not exposed subjects.

Increased lipid peroxidation in the blood of exposed subjects warns that oxygen free radicals have increased in the body and thus might attack cells, which, in the longterm, results in multi-organ damage. The remaining blood total antioxidant capacity at normal values is promising and means that other non-thiol antioxidants, such as uric acid, transferrin, ceruloplasmin, albumin, and vitamin antioxidants, such as a-tocopherol and ascorbic acid, have been stimulated to maintain the total anti-oxidant power of the body at normal state.