Volume 72, Issue 6

Twenty-four men and 24 women, all nonsmoking, and maintaining normal dietary habits were assigned to 3 groups of 16. Each group comprising 4 males with "low" cholesterol levels (<6 mmol/L) matched for age and build with 4 males with "high" cholesterol levels (>6 mmol/L) and 8 similarly matched females. A three-treatment, three-treatment period, cross-over design was adopted. The three treatments were placebo, 60 mg vitamin C/day (the recommended daily allowance) and 6 g vitamin C/day for 14 days with 6 weeks between treatments. Blood samples were taken at the end of each treatment period. Vitamin C supplementation significantly increased plasma vitamin C concentrations and total antioxidant capacity, but did not affect cholesterol status or plasma ras p21 protein levels. There was a nonsignificant dose-related decrease in plasma lipid peroxidation breakdown products. DNA damage, measured in lymphocytes by the Comet assay and chromosome aberration test, was not increased after vitamin C supplementation. Sensitivity to hydrogen peroxide (in the Comet assay) was also unaffected, but sensitivity to chromosome aberration induced by bleomycin was increased by supplementation. A significant gender difference was found in plasma vitamin C levels, antioxidant capacity, and number of chromosome aberrations. Results were independent of low and high cholesterol status.

Polycyclic aromatic hydrocarbons (PAHs), dioxins, dibenzofurans, and polychlorinated biphenyls (PCBs) present in polluted environment induce cytochrome P4501A (CYP1A) isozyme in fish, which in turn results in a marked increased production of carcinogenic metabolites from PAHs. The induction of hepatic CYP1A in fish by certain classes of chemicals has been suggested as an early warning system, a "most sensitive biological response" for assessing environmental contamination conditions. This has implications for human fish consumption, as well as for the health status of aquatic organisms. Correlation between elevated CYP1A and altered steroid metabolism and decreased reproductive success has been pointed out. The induction of CYP1A and associated enzyme activities has now been confirmed in a number of field studies. Cases where these biomarkers have been studied in field conditions will be presented. Special emphasis will be given to field studies in which the induction of CYP1A activity, 7-ethoxyresorufin O-deethylase (EROD) activities and immunochemical detection of CYP1A in leaping mullet and common sole are used as a biomarker for PAH- and/or PCB-type pollutants along the Izmir Bay on the Aegean Sea.

Mutations of the p53 tumor suppressor gene occur in a great majority of human cancers. The protein product of p53 gene is involved in DNA damage response. Consequently, p53 gene may be a preferred target for environmental carcinogens, which also act as DNA-damaging agents. This is probably why p53 mutations are frequent in cancers linked to environmental carcinogens. Moreover, these carcinogens leave molecular fingerprints on the p53 gene. Thus, the study of p53 mutation spectra has been a useful approach to implicate suspected carcinogens to different human cancers. This review provides further insight into the significance of p53 mutation spectra in ten common human malignancies (skin, liver, lung, bladder, breast, head and neck, esophagus, stomach and colorectal cancers, and hematological malignancies), in relation with environmental carcinogens.

Methamphetamine (METH) is a potent psychostimulant known to produce neurotoxicity. The dopaminergic pathway is particularly sensitive to METH. Recent studies showed that 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS), provided protection against METH neurotoxicity both in vitro and in vivo. The present studies were conducted to determine the nNOS activity in various regions of the brain of young adult male Sprague-Dawley rats treated with different doses of METH. Rats were injected ip with 5, 10, 20, and 40 mg/kg and 24 h after the rats were sacrificed and the brain regions (hippocampus, frontal cortex, and cerebellum) were quickly dissected. The cytosolic fractions were prepared, and the nNOS activity was determined using the 3H-citrulline assay. The results showed that nNOS activity was significantly increased in all three brain regions of rats treated with METH. The increase was dose dependent reaching a maximum of 40-100% over the control values. Rats treated with 7NI 30 min prior to METH injection provided protection against the toxicity and also showed a reduction of nNOS activity. The activation of nNOS is known to increase the synthesis of NO which is involved in the regulation of several neurotransmitter pathways including catecholaminergic system. Reducing the METH-induced production of NO by pretreatment with selective inhibitor of nNOS, 7-NI, provided protection against METH neurotoxicity.

The carcinogenicity of nickel, chromium, arsenic, cobalt, and cadmium compounds has long been recognized. Nevertheless, the mechanisms involved in tumor formation are not well understood. The carcinogenic potential depends on metal species; major determinants are oxidation state and solubility. Two modes of action seem to be predominant: the induction of oxidative DNA damage and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA-damaging agents. Nucleotide excision repair (NER) is inhibited at low, non-cytotoxic concentrations of nickel(II), cadmium(II), cobalt(II), and arsenic(III); the repair of oxidative DNA base modifications is disturbed by nickel(II) and cadmium(II). One reason for repair inhibition appears to be the displacement of zinc(II) and magnesium(II). Potentially sensitive targets are so-called zinc finger structures present in several DNA repair enzymes such as the mammalian XPA protein and the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein); detailed studies revealed that each zinc finger protein exerts unique sensitivities toward toxic metal ions. Taken together, toxic metal ions may lower the genetic stability by inducing oxidative DNA damage and by decreasing the repair capacity towards DNA lesions induced by endogenous and exogenous mutagens, which may in turn increase the risk of tumor formation.

The inadvertent exposure of a large cohort of individuals to hexachlorobenzene (HCB) in the mid-1950s in southeastern Turkey remains an environmental disaster that continues to fascinate and provide interesting observations concerning this ubiquitous chemical. A brief history of the exposure is presented with particular reference to the initial presentation of Pembe Yara and Porphyria Cutanea Tarda and later to reproductive performance in humans and sub-human primates. Differential toxicity is present in the oocytes of monkeys, with more severe damage identified in primordial germ cells rather than in growing oocytes. However, this observation did not express itself in women, as there was no increased incidence of premature menopause among those exposed. Germ cell toxicity remains a possible outcome of exposure, however. The serum HCB levels measured in exposed individuals predicted the lifetime risk of spontaneous abortion, not only in exposed individuals but also in the control populations, indicating that a possible population effect is present.

Acute Cd exposure produces liver injury, whereas chronic Cd exposure damages the kidney but not the liver. Previous experiments suggest that the low-molecular-weight, metal-binding protein metallothionein (MT) in liver protects against liver injury, but is responsible for the kidney injury observed after chronic Cd exposure. Thus, prior to the development of MT-transgenic and MT-knockout mice models, MT's role was always assumed to be a toxicological paradox, hepatoprotection but nephrotoxicity. The development of MT-transgenic and MT-knockout mice models has reconfirmed MT's protective role against Cd-induced hepatotoxicity, but it has challenged MT's suggested role in Cd-induced nephrotoxicity. In this communication, recent data using these genetically altered mice models indicate that MT protects against not only the Cd-induced hepatotoxicity, but also nephrotoxicity, hematotoxicity, immunotoxicity, and bone damage.

The German Environmental Specimen Bank (GESB) has been an important tool in contaminant monitoring and ecotoxicological research for more than one decade. The annual monitoring program provides a long-term database to determine trends in contaminant burdens in biota samples. Results of ten years of experience in the determination of chlorinated hydrocarbons (CHCs) in herring gull eggs collected in the North Sea and the Baltic Sea are presented. In addition, the study reports CHC concentrations in bream livers from the River Elbe between 1993-1997. Most of the compounds studied show a significant decline over time, especially in samples from East Germany. For specimens taken in West Germany, only small decreases or no changes of CHC levels were observed.

To investigate an involvement of catecholamines and/or the cyclic adenosine monophosphate (cAMP) systems in the development of drug dependence, we examined whether phencyclidine (PCP) and morphine dependence were developed in tyrosine hydroxylase (TH) heterozygous (TH +/- ) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP +/- ) mice. PCP (8 mg/kg) induced place preference in wild-type mice pretreated with PCP (10 mg/kg/day for 28 days) and increased the level of cAMP in the striatum, but not in the thalamus/hypothalamus. In TH +/- and CBP +/- mice, however, we could not find PCP-induced place preference. The increased level of cAMP in the striatum was observed in CBP +/- , but not TH +/- mice. When wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased jumping, rearing, and forepaw tremor counts as a sign of withdrawal and an increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. In TH +/- and CBP +/- mice, however, jumping and forepaw tremor counts were decreased compared to in wild-type mice. An increase in the level of cAMP in the thalamus/hypothalamus in CBP +/- , but not in TH +/- mice was observed. These results suggest that catecholamines and CBP are involved in the development of PCP and morphine dependence, and that changes in catecholaminergic and/or cAMP systems induced by repeated PCP and morphine treatments play an important role in the addiction to PCP and morphine.

Amphetamine analogues are able to induce signs of neurotoxicity in the brain. In order to understand this type of neurotoxicity, the interaction of amphetamine with its molecular targets must be elucidated. These molecular targets are plasmalemmal and vesicular monoamine transporters. We investigated the interaction of amphetamine with these transporters in cells transfected with the respective cDNA. Superfusion and whole-cell, patch-clamp experiments were performed, and the toxicity of substrates of the transporters was studied. Amphetamine was taken up by dopamine transporter-expressing cells in a sodium-dependent and cocaine-blockable manner. Furthermore, it elicited inward currents in these cells concentration-dependently. Correlation of uptake, release, and patch-clamp experiments suggest that ion fluxes induced by substrate-gating on transporters may significantly contribute to the releasing action of amphetamine and of other transporter substrates. Dopamine accumulation into serotoninergic terminals depleted of serotonin by 3,4-methylenedioxymethamphetamine was discussed as a mechanism of Ecstasy-toxicity. This is in agreement with a toxic effect of intracellular dopamine which could be demonstrated on our transporter-overexpressing cells. These results, apart from their relevance for the toxicity by amphetamine analogues, may also have bearings on the mechanisms in neurodegenerative diseases affecting monoamine transmitters.

Risk assessment is an important tool in deciding how to allocate resources to controlling risks. In most cases it is based on hazard data derived from animal experiments and on exposure data from an assessment of the likely or actual exposure of the population of interest. Recent advances have improved the understanding of the use of the no adverse effect level (NOAEL) and safety factor for risk assessment by providing a scientific justification of the 100-fold safety factor. Concern about the risks of exposure by various routes simultaneously (aggregate exposure) and the risks of exposure to mixtures (cumulative risk assessment) have lead to new approaches to these issues. For many years, risk assessment of genotoxic carcinogens has relied on low-dose extrapolation using mathematical models. Recently, these methods are being reconsidered and, in some cases, replaced with the NOAEL/safety factor approach combined with all information on the mechanism of action and the magnitude of the response. It is vitally important to ensure that risk assessment provides accurate and unbiased estimates of risk of exposure so that appropriate measures can be taken to control the risks.

Modern sophisticated analytical tools have enabled toxicologists to investigate hair specimens for the presence of drugs. Although great sensitivity and specificity in hair analysis have been already achieved, some concerns about bias due to hair color, lack of reference materials, and dose versus concentration relationship make the quantitative data sometimes debatable. The most commonly held opinion in this field nowadays indicates that hair analysis has sufficient scientific validity. Experts should always be aware and take into account limitations of hair analysis results and its evaluation. Unresolved scientific issues, however, should not obstruct the admissibility of strongly positive test results. Recent applications of hair testing include forensic investigations, epidemiological studies, gestational drug exposure, legal issues, clinical drug monitoring, and historical research. In this paper, the use of sectional hair tests to assess exposure to drugs of abuse (evaluation of toxicomania) and to assess compliance with carbamazepine, phenytoin and valproic acid therapy regime is presented. We conclude that hair drug versus time profiles give strong evidence that confirm chronic abuse, the diagnosis of drugs of abuse poisoning, and the state of addiction (toxicomania). Additionally, they may be used as a marker of the dosage history and the compliance of patients under long-term treatment with carbamazepine and phenytoin.

The subject field of clinical allergology deals with many hundred different allergens from all parts of the human environment and the number steadily increases. Not all of the allergens are strictly defined in chemical terms and procedures for detection of antibodies against the allergens in the human vary. This document deals with the presentation of request and report on such properties according to some international rules and the allocation of code values representing the concept delineated. The coding scheme thus prepared is imperfect and needs further elaboration as allergens become more well defined. It is a step toward harmonization, in particular as concerns the coding system applied. The net outcome is a coding scheme for use in electronic transmission. Preface The present document is part sixteen (XVI) of a series on properties and units in the clinical laboratory sciences initiated in 1987. > View series titles (view corresponding project) The NCCLS code values are reproduced with permission from NCCLS publication I/LA20-P. Foreword and Scope Basic research in biology and medicine and innovations in laboratory methodology have greatly increased the range of properties available to medical practitioners to help them in decisions on diagnosis, treatment and prevention of disease. The plethora is now such that the individual doctor has insight in or understanding of only a limited number of properties offered to him or her from the various clinical laboratory specialities. In the laboratory, local terms (jargon) may be well understood among colleagues, but they are not appropriate for communication with the outside world. Likewise, a laboratory and its local community of users, such as hospital or community physicians, may use a "local dialect" of the language of clinical laboratory sciences which is well understood by all concerned, but when the communication possibilities are wider, even transnational, risks of serious misunderstanding arise. In addition, the terminology used by one laboratory speciality may vary even within the speciality, and may be incomprehensible to another speciality. This inconsistency is a minor inconvenience to the laboratory specialities, each one essentially operating within its own area of activity. However, for the user this inconsistency is highly unsatisfactory and may hinder treatment of the patient. It is therefore essential to promote clear, unambiguous, meaningful and fully informative communication. Also coherence of statements made within and between medical specialities, and uniformity in structure of presentation is to be strived for. This coherence will facilitate transfer of information over cultural, alphabetic and language areas. The purpose of this document is to apply the syntax structures for request and report recommended by the European standards ENV 1614:1995 and ENV 12435:1996 and by IUPAC-IFCC, providing formats and names of properties observed in the domain of clinical allergology, in order to facilitate unequivocal written or electronic communication between health care professionals. The systematic names recommended here are primarily for the purpose of unambiguous data exchange. Their use in routine language by clinicians or laboratory practitioners is optional but encouraged.