Antidepressant effect of repetitive transcranial magnetic stimulation is not impaired by intake of lithium or antiepileptic drugs.

INTRODUCTION: The effect of concomitant medication on repetitive transcranial magnetic stimulation (rTMS) outcomes in depression remains understudied. Recent analyses show attenuation of rTMS effects by antipsychotic medication and benzodiazepines, but data on the effects of antiepileptic drugs and lithium used as mood stabilizers or augmenting agents are sparse despite clinical relevance. Preclinical electrophysiological studies suggest relevant impact of the medication on treatment, but this might not translate into clinical practice. We aimed to investigate the role of lithium (Li), lamotrigine (LTG) and valproic acid (VPA) by analyzing rTMS treatment outcomes in depressed patients. METHODS: 299 patients with uni- and bipolar depression treated with rTMS were selected for analysis in respect to intake of lithium, lamotrigine and valproic acid. The majority (n = 251) were treated with high-frequency (10-20 Hz) rTMS of the lDLPFC for an average of 17 treatment sessions with a figure-of-8 coil with a MagVenture system aiming for 110% resting motor threshold, and smaller groups of patients were being treated with other protocols including intermittent theta-burst stimulation and bilateral prefrontal and medial prefrontal protocols. For group comparisons, we used analysis of variance with the between-subjects factor group or Chi-Square Test of Independence depending on the scales of measurement. For post-hoc tests, we used least significant difference (LSD). For differences in treatment effects between groups, we used an ANOVA with the between-subjects factor group (groups: no mood stabilizer, Li, LTG, VPA, Li + LTG) the within-subjects factor treatment (pre vs. post treatment with rTMS) and also Chi-Square Tests of independence for response and remission. RESULTS: Overall, patients showed an amelioration of symptoms with no significant differences for the main effect of group and for the interaction effect treatment by group. Based on direct comparisons between the single groups taking mood stabilizers against the group taking no mood stabilizers, we see a superior effect of lamotrigine, valproic acid and combination of lithium and lamotrigine for the response and remission rates. Motor threshold was significantly and markedly higher for patients taking valproic acid. CONCLUSION: Being treated with lithium, lamotrigine and valproic acid had no relevant influence on rTMS treatment outcome. The results suggest there is no reason for clinicians to withhold or withdraw these types of medication from patients who are about to undergo a course of rTMS. Prospective controlled work on the subject is encouraged.

Concomitant lorazepam use and antidepressive efficacy of repetitive transcranial magnetic stimulation in a naturalistic setting.

BACKGROUND/OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective therapeutic intervention for the treatment of depression. Preliminary data suggest that the efficacy of rTMS is reduced in patients taking benzodiazepines (BZD). Here, we use real-world data from a large sample to investigate the influence of lorazepam on the effectiveness of rTMS. METHODS: From a retrospective cohort of clinically depressed patients that were treated with rTMS, we compared 176 patients not taking any BZD with 73 patients taking lorazepam with respect to changes in the Hamilton Depression Rating Scale (HRDS). RESULTS: Both groups improved during rTMS according to HRDS scores, but the amelioration of symptoms was significantly less pronounced in patients taking lorazepam (18% vs. 38% responders in the non-lorazepam group). We could not see any association of intake regimen of lorazepam with response in rTMS. CONCLUSION: Our observational study suggests that intake of lorazepam impedes the response to rTMS. The impact of lorazepam and other BZD on rTMS should receive more attention and be further investigated in prospective, hypothesis-based treatment studies to determine causal relationships between medication treatments and outcome. This could lead to specific recommendations for pharmacological treatment for depressed patients undergoing rTMS.

[Intracranial hemorrhage masquerading as STEMI]. / EKG-Veränderungen bei intrakranieller Blutung.

A 56-year-old woman was found unconscious and promptly intubated. The electrocardiogram showed ST elevations in I, aVL, V1-V4. Thus, lysis therapy was performed. After admission to the intensive care unit, the patient was reassessed. Laboratory evaluation confirmed elevated troponin T. However, coronary angiography showed no coronary artery disease, whereas cerebral computed tomography revealed massive intracranial hemorrhage without neurosurgical treatment option. Brain death was confirmed after 54 hours. This case highlights electrocardiographic changes in intracranial hemorrhage that may be masquerading as STEMI.

Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

[Hypothermia under olanzapine treatment: clinical case series and review of current literature]. / Hypothermie unter Olanzapin : Eine Fallserie mit Literaturübersicht.

BACKGROUND: Antipsychotic drugs may lead to hypothermia as well as hyperthermia. Although known for decades and clinically highly relevant, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are still far from being fully understood. In clinical practice, much attention is paid to antipsychotic drug-induced elevation of body core temperature as observed in the neuroleptic malignant syndrome (NMS). But also hypothermia is a clinically highly relevant adverse reaction to antipsychotic drugs. MATERIAL AND METHODS: Here we report a case series of three patients who developed severe hypothermia after administration of olanzapine. A review of the current literature is given with a focus on risk factors for the development of antipsychotic drug-induced hypothermia and its pathophysiologic mechanisms. RESULTS: A 51-year-old female patient suffering from catatonic schizophrenia, cachectic nutritional condition and hypothyroidism developed severe hypothermia of 30.0°C body core temperature after administration of 30 mg olanzapine per day under comedication with lorazepam and L-thyroxine. A 48-year-old female patient with catatonic schizophrenia showed hypothermia of 31.0°C (rectal measurement) after single-dose administration of olanzapine 10 mg orally and a total of 3 mg lorazepam (1-1-1 mg). The third case report describes a 69-year-old male patient with acute delusional disorder exhibiting hypothermia of 33.0°C (rectal measurement) in combination with a reversible atrioventricular block grade III without any further comedication. CONCLUSION: A review of the current literature reveals that thermoregulatory disturbances as sequelae of antipsychotic drug administration depend on individual disposition as well as various independent risk factors such as environmental temperature, somatic comorbidities, endocrinological abnormalities (e.g. hypothyroidism) and structural damage of the brain. A complex interaction of dopaminergic regulatory mechanisms in the ventral hypothalamus and peripheral vaso- and sudomotor adjustments seems to be causative. Hypothermia following antipsychotic drug administration represents a serious adverse drug reaction and a potentially life-threatening event.

Kinetics of propylene oxide metabolism in microsomes and cytosol of different organs from mouse, rat, and humans.

Kinetics of the metabolic inactivation of 1,2-epoxypropane (propylene oxide; PO) catalyzed by glutathione S-transferase (GST) and by epoxide hydrolase (EH) were investigated at 37 degrees C in cytosol and microsomes of liver and lung of B6C3F1 mice, F344 rats, and humans and of respiratory and olfactory nasal mucosa of F344 rats. In all of these tissues, GST and EH activities were detected. GST activity for PO was found in cytosolic fractions exclusively. EH activity for PO could be determined only in microsomes, with the exception of human livers where some cytosolic activity also occurred, representing 1-3% of the corresponding GST activity. For GST, the ratio of the maximum metabolic rate (V(max)) to the apparent Michaelis constant (K(m)) could be quantified for all tissues. In liver and lung, these ratios ranged from 12 (human liver) to 106 microl/min/mg protein (mouse lung). Corresponding values for EH ranged from 4.4 (mouse liver) to 46 (human lung). The lowest V(max) value for EH was found in mouse lung (7.1 nmol/min/mg protein); the highest was found in human liver (80 nmol/min/mg protein). K(m) values for EH-mediated PO hydrolysis in liver and lung ranged from 0.83 (human lung) to 3.7 mmol/L (mouse liver). With respect to liver and lung, the highest V(max)/K(m) ratios were obtained for GST in mouse and for EH in human tissues. GST activities were higher in lung than in liver of mouse and human and were alike in both rat tissues. Species-specific EH activities in lung were similar to those in liver. In rat nasal mucosa, GST and EH activities were much higher than in rat liver.

Quantitation of DNA and hemoglobin adducts and apurinic/apyrimidinic sites in tissues of F344 rats exposed to propylene oxide by inhalation.

Propylene oxide (PO) is a relatively weak mutagen that induces nasal tumor formation in rats during long-term inhalation studies at high exposures (> or =300 p.p.m.), concentrations that also cause cytotoxicity and increases in cell proliferation. Direct alkylation of DNA by PO leads mainly to the formation of N:7-(2-hydroxypropyl)guanine (7-HPG). In this study, the accumulation of 7-HPG in tissues of male F344 rats exposed to 500 p. p.m. PO (6 h/day, 5 days/week for 4 weeks) by the inhalation route was measured by gas chromatography-high resolution mass spectrometry (GC-HRMS). In animals killed up to 7 h following the end of the last exposure the levels of 7-HPG (pmol/micromol guanine) in nasal respiratory tissue, nasal olfactory tissue, lung, spleen, liver and testis DNA were 606.2 +/- 53.0, 297.5 +/- 56.5, 69.8 +/- 3.8, 43.0 +/- 3.8, 27.5 +/- 2.4 and 14.2 +/- 0.7, respectively. The amounts of 7-HPG in the same tissues of animals killed 3 days after cessation of exposure were 393.3 +/- 57.0, 222.7 +/- 29.5, 51.5 +/- 1.2, 26.7 +/- 1.0, 18.0 +/- 2.6 and 10.4 +/- 0.1. A comparable rate of disappearance of 7-HPG was found among all tissues. DNA from lymphocytes pooled from four rats killed at the end of the last exposure was found to have 39.6 pmol adduct/micromol guanine. Quantitation of DNA apurinic/apyrimidinic sites, potentially formed after adduct loss by chemical depurination or DNA repair, showed no difference between tissues from control and exposed rats. The level of N:-(2-hydroxypropyl)valine in hemoglobin of exposed rats was also determined using a modified Edman degradation method followed by GC-HRMS analysis. The value obtained was 90.2 +/- 10.3 pmol/mg globin. These data demonstrate that nasal respiratory tissue, which is the target tissue for carcinogenesis, has a much greater level of alkylation of DNA than non-target tissues.

A physiological toxicokinetic model for exogenous and endogenous ethylene and ethylene oxide in rat, mouse, and human: formation of 2-hydroxyethyl adducts with hemoglobin and DNA.

Ethylene (ET) is a gaseous olefin of considerable industrial importance. It is also ubiquitous in the environment and is produced in plants, mammals, and humans. Uptake of exogenous ET occurs via inhalation. ET is biotransformed to ethylene oxide (EO), which is also an important volatile industrial chemical. This epoxide forms hydroxyethyl adducts with macromolecules such as hemoglobin and DNA and is mutagenic in vivo and in vitro and carcinogenic in experimental animals. It is metabolically eliminated by epoxide hydrolase and glutathione S-transferase and a small fraction is exhaled unchanged. To estimate the body burden of EO in rodents and human resulting from exposures to EO and ET, we developed a physiological toxicokinetic model. It describes uptake of ET and EO following inhalation and intraperitoneal administration, endogenous production of ET, enzyme-mediated oxidation of ET to EO, bioavailability of EO, EO metabolism, and formation of 2-hydroxyethyl adducts of hemoglobin and DNA. The model includes compartments representing arterial, venous, and pulmonary blood, liver, muscle, fat, and richly perfused tissues. Partition coefficients and metabolic parameters were derived from experimental data or published values. Model simulations were compared with a series of data collected in rodents or humans. The model describes well the uptake, elimination, and endogenous production of ET in all three species. Simulations of EO concentrations in blood and exhaled air of rodents and humans exposed to EO or ET were in good agreement with measured data. Using published rate constants for the formation of 2-hydroxyethyl adducts with hemoglobin and DNA, adduct levels were predicted and compared with values reported. In humans, predicted hemoglobin adducts resulting from exposure to EO or ET are in agreement with measured values. In rodents, simulated and measured DNA adduct levels agreed generally well, but hemoglobin adducts were underpredicted by a factor of 2 to 3. Obviously, there are inconsistencies between measured DNA and hemoglobin adduct levels.

Tissue distribution of DNA adducts in male Fischer rats exposed to 500 ppm of propylene oxide: quantitative analysis of 7-(2-hydroxypropyl)guanine by 32P-postlabelling.

7-(2-Hydroxypropyl)guanine (7-HPG) constitutes the major adduct from alkylation of DNA by the genotoxic carcinogen, propylene oxide. The levels of 7-HPG in DNA of various organs provides a relevant measure of tissue dose. 7-Alkylguanines can induce mutation through abasic sites formed from spontaneous depurination of the adduct. In the current study the formation of 7-HPG was investigated in male Fisher 344 rats exposed to 500 ppm of propylene oxide by inhalation for 6 h/day, 5 days/week, for up to 20 days. 7-HPG was analyzed using the 32P-postlabelling assay with anion-exchange cartridges for adduct enrichment. In animals sacrificed directly following 20 days of exposure, the adduct level was highest in the respiratory nasal epithelium (98.1 adducts per 10(6) nucleotides), followed by olfactory nasal epithelium (58.5), lung (16.3), lymphocytes (9.92), spleen (9.26), liver (4.64), and testis (2.95). The nasal cavity is the major target for tumor induction in the rat following inhalation. This finding is consistent with the major difference in adduct levels observed in nasal epithelium compared to other tissues. In rats sacrificed 3 days after cessation of exposure, the levels of 7-HPG in the aforementioned tissues had, on the average, decreased by about one-quarter of their initial concentrations. This degree of loss closely corresponds to the spontaneous rate of depurination for this adduct (t 1/2 = 120 h), and suggests a low efficiency of repair for 7-HPG in the rat. The postlabelling assay used had a detection limit of one to two adducts per 10(8) nucleotides, i.e. it is likely that this adduct could be analyzed in nasal tissues of rats exposed to less than 1 ppm of propylene oxide.

Propylene oxide: mutagenesis, carcinogenesis and molecular dose.

The results from mutagenic and carcinogenic studies of propylene oxide (PO) and the current efforts to develop molecular dosimetry methods for PO-DNA adducts are reviewed. PO has been shown to be active in several bacterial and mammalian mutagenicity tests and induces site of contact tumors in rodents after long-term administration. Quantitation of N7-(2-hydroxypropyl)guanine (7-HPG) in nasal and hepatic tissues of male F344 rats exposed to 500 ppm PO (6 h/day; 5 days/week for 4 weeks) by inhalation was performed to evaluate the potential of high concentrations of PO to produce adducts in the DNA of rodent tissues and to obtain information necessary for the design of molecular dosimetry studies. The persistence of 7-HPG in nasal and hepatic tissues was studied in rats killed three days after cessation of a 4-week exposure period. DNA samples from exposed and untreated animals were analyzed for 7-HPG by two different methods. The first method consisted of separation of the adduct from DNA by neutral thermal hydrolysis, followed by electrophoretic derivatization of the adduct and gas chromatography-high resolution mass spectrometry (GC-HRMS) analysis. The second method utilized 32P-postlabeling to quantitate the amount of this adduct in rat tissues. Adducts present in tissues from rats killed immediately after cessation of exposure were 835.4 +/- 80.1 (respiratory), 396.8 +/- 53.1 (olfactory) and 34.6 +/- 3.0 (liver) pmol adduct/mumol guanine using GC-HRMS. Lower values, 592.7 +/- 53.3, 296.5 +/- 32.6 and 23.2 +/- 0.6 pmol adduct/mumol guanine were found in respiratory, olfactory and hepatic tissues of rats killed after three days of recovery. Analysis of the tissues by 32P-postlabeling yielded the following values: 445.7 +/- 8.0 (respiratory), 301.6 +/- 49.2 (olfactory) and 20.6 +/- 1.8 (liver) pmol adduct/mumol guanine in DNA of rats killed immediately after exposure cessation and 327.1 +/- 21.7 (respiratory), 185.3 +/- 29.2 (olfactory) and 15.7 +/- 0.9 (liver) pmol adduct/mumol guanine after recovery. Current methods of quantitation did not provide evidence for the endogenous formation of this adduct in control animals. These studies demonstrated that the target tissue for carcinogenesis has much greater alkylation of DNA than liver, a tissue that did not exhibit a carcinogenic response.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition.

Contents of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of 16 further congeners--polychlorinated dibenzodioxins and dibenzofuranes (PCDD/PCDF)--were determined in lipids of adipose tissue and of livers of 3 stillborns and of 17 infants (0.43-44 weeks old) who died from sudden infant death syndrome. International toxic equivalents (I-TEq) calculated for the sum of TCDD together with all of the 16 congeners (1.55-29.63 ng/kg lipids of adipose tissue, n = 20; 2.05-57.73 ng/kg liver lipids, n = 19) were within the range of or lower than the values published for adults. TCDD concentrations in lipids of breast-fed infants were higher (0.38-4.1 ng/kg lipids of adipose tissue, n = 9; 0.49-3.9 ng/kg liver lipids, n = 8) compared to non breast-fed subjects (0.16-0.76 ng/kg lipids of adipose tissue, n = 8; 0.29-0.71 ng/kg liver lipids, n = 7). Neither I-TEq values nor TCDD concentrations exceeded values published for adults. Since even in stillborns PCDD/PCPF were found (I-TEq, 9.70-10.83 ng/kg lipids of adipose tissue, 6.17-8.83 ng/kg liver lipids; TCDD, 1.3-2.1 ng/kg lipids of adipose tissue, 0.76-1.5 ng/kg liver lipids; n = 3), transplacental exposure has to be deduced. All of the findings concerning TCDD concentrations in the organism become intelligible on the basis of a physiological toxicokinetic model which was developed to describe the body burden of TCDD for the entire human lifetime in dependence of TCDD uptake from contaminated nutrition. The model reflects sex and age dependent changes in the following parameters: body weight, volumes of liver, adipose and muscle tissue, food consumption, and excretion of faeces. TCDD is supposed to be taken up orally, to be distributed freely in lipids of the organism and to be eliminated unchanged by excretion in lipids of faeces as well as by metabolism in the liver. The model was used to predict the half-life of elimination of TCDD (4 months in newborns increasing to approximately 5 years in adults) and concentrations of this compound in lipids of adipose tissue, blood, liver and faeces at different ages. Furthermore, the influence of breast-feeding on the TCDD burden of a mother, her milk and her child was simulated. The model was validated by means of own data gained in adipose tissue and livers of infants and also using a series of values measured by other authors in mother's milk and in tissues and faeces of infants and adults. Predictions as well as experimental findings demonstrate a distinct increase in the TCDD body burden of breast-fed infants. Generally, it can be concluded for the excretion of unchanged, non-volatile, non protein bound highly lipophilic compounds that their half-life is short in infants (approximately 5 months) and increases to approximately 10 years reached between 40 and 60 years of age.

Toxicokinetics of isoprene in rodents and humans.

A physiological toxicokinetic model (PT model) was developed for inhaled isoprene in mouse, rat and man. Partition coefficients blood:air and tissue:blood were determined in vitro by a headspace method. Parameters of a saturable isoprene metabolism in B6C3F1 mice, Sprague-Dawley rats and volunteers were obtained from gas uptake experiments in closed systems, analyzed by means of a two-compartment model. Incorporation of these parameters into the PT model revealed that isoprene was metabolized not only in the liver but also in extrahepatic organs. Endogenous production of isoprene in man was quantified from experiments with volunteers breathing into a closed system. The PT model was validated for mice, rats and humans by comparing simulated values with data determined by other authors.

A physiological toxicokinetic model for 1,3-butadiene in rodents and man: blood concentrations of 1,3-butadiene, its metabolically formed epoxides, and of haemoglobin adducts--relevance of glutathione depletion.

A physiological toxicokinetic (PT) model is presented describing disposition and metabolism of 1,3-butadiene (BU) and 1,2-epoxy-3-butene (BMO) in rat, mouse and man, and of 1,2:3,4-diepoxybutane (BDI) in mice. It contains formation of BMO and BDI, intrahepatocellular first-pass hydrolysis of BMO, conjugation of BMO with glutathione (GSH) and GSH-turnover in the liver. Tissue:air partition coefficients of BU and BMO were determined experimentally. Haemoglobin (HB) adducts of BMO in rodents following exposure to BU were simulated and compared with published data. The model is compared with those published earlier. An attempt was made to compare the carcinogenic potential of BU in mice and rats with respect to the carcinogenic potentials of both epoxides.

Toxicokinetic models for volatile industrial chemicals and reactive metabolites.

Two approaches of compartmental toxicokinetic modeling of gaseous compounds are presented which are suitable for kinetic analysis of concentration-time data measured in the air of closed exposure systems. The first approach is based on a two-compartment model with physiological gas uptake, the second on a physiologically-based toxicokinetic model. Both models can be used for the description of inhalation, accumulation, exhalation and metabolism of gaseous compounds together with the toxicokinetics of metabolites. Interspecies extrapolation is based on physicochemical, physiological and biochemical parameters. The advantage of the two-compartment model is its limited number of variables and its experimentally easy applicability. Its disadvantage is the impossibility to predict tissue specific concentrations. The advantage of the physiologically-based model is its usability for predictions and for the description of tissue specific concentrations. However, it entails great effort, since a series of parameters has to be determined before meaningful model calculations can be carried out.

Biomarkers as tools in human health risk assessment.

Evaluation of occupational or environmental risk due to exposure to chemicals requires sufficient information on the toxic profiles, mechanisms of action, toxicokinetics, dose-response relation, exposure, and the target dose. Usually exposure is estimated by measuring concentrations of the agent in air, food, water, soil, dust, or other media with which a population or an individual is in contact. However, this external exposure is only a rough estimate for the internal exposure (agent dose or its metabolite at the critical target in the organism). Factors of influence are bioavailability of the chemicals, variations in concentrations and routes of exposure, physical activity, and individual variation in rates of metabolism, distribution, and excretion. All these affect the concentration of the toxic agent at the critical target, which is the most precise information for risk assessment. Thus, internal exposure is best measured by determining the concentration of the toxicant or its ultimate metabolite at the critical site in the target organ or by determining adducts with cellular macromolecules such as proteins, amino acids, DNA, or its bases. The latter are easily available in experimental toxicology from animal experiments but only occasionally from humans. For health surveillance such data usually are not available, because they require invasive procedures such as biopsies. Therefore, more accessible body fluids or tissue are used, such as blood, urine, or adipose tissue, or adducts with macromolecules such as albumin or hemoglobin in the blood, DNA adducts in peripheral lymphocytes, or altered DNA bases in urine such as 8-hydroxyguanine. All of these are indicators for exposure, whereas risk can only be estimated if the correlation between their deviations from normal and the dose-response at the critical target is known.

New scientific arguments for regulation of ethylene oxide residues in skin-care products.

Ethylene oxide (EO) occurs as a contaminant of skin-care products because current commercial preparations of polyglycol ethers may contain ethylene oxide monomer residues, up to the order of 1 ppm. Using current regulatory worst-case assumptions, the presence of EO in skin-care products might lead to a maximal human daily external ethylene oxide dose of about 2.8 micrograms, and a consecutive maximal daily absorbed dose of 0.39 microgram. Two methods of toxicokinetic analysis have been used to compare this possible EO load by use of skin-care products with the inevitable load of EO which is produced endogenously in the organism. On the basis of a previous assessment of the endogenous production of ethylene and ethylene oxide (Filser et al. 1992) it is inferred that the absorbed EO dose of 0.39 microgram is about 1/30 of the unavoidable human endogenous load by endogenous EO. Alternatively, for a second calculation molecular dosimetry data have been used which were based on experimental quantification of the hydroxyethyl adduct of EO to the N-terminal valine of hemoglobin (HOEtVal) in rats. If the worst-case assumptions for human EO absorption from skin-care products are transferred to the rat species, the associated internal EO doses are about 1/110 of the internal EO doses which were calculated from the background HOEtVal concentrations observed in untreated animals. The divergence between both lines of calculation is mainly due to differences in HOEtVal background concentrations between man and rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Species-specific pharmacokinetics of styrene in rat and mouse.

The pharmacokinetics of styrene were investigated in male Sprague-Dawley rats and male B6C3F1 mice using the closed chamber technique. Animals were exposed to styrene vapors of initial concentrations ranging from 550 to 5000 ppm, or received intraperitoneal (i.p.) doses of styrene from 20 to 340 mg/kg or oral (p.o.) doses of styrene in olive oil from 100 to 350 mg/kg. Concentration-time courses of styrene in the chamber atmosphere were monitored and analyzed by a pharmacokinetic two-compartment model. In both species, the rate of metabolism of inhaled styrene was concentration dependent. At steady state it increased linearly with exposure concentration up to about 300 ppm; more than 95% of inhaled styrene was metabolized and only small amounts were exhaled unchanged. At these low concentrations transport to the metabolizing enzymes and not their metabolic capacity was the rate limiting step for metabolism. Pharmacokinetic behaviour of styrene was strongly influenced by physiological parameters such as blood flow and especially the alveolar ventilation rate. At exposure concentrations of styrene above 300 ppm the rate of metabolism at steady state was progressively limited by biochemical parameters of the metabolizing enzymes. Saturation of metabolism (Vmax) was reached at atmospheric concentrations of about 700 ppm in rats and 800 ppm in mice, Vmax being 224 mumol/(h.kg) and 625 mumol/(h.kg), respectively. The atmospheric concentrations at Vmax/2 were 190 ppm in rats and 270 ppm in mice. Styrene accumulates preferentially in the fatty tissue as can be deduced from its partition coefficients in olive oil:air and water:air which have been determined in vitro at 37 degrees C to be 5600 and 15. In rats and mice exposed to styrene vapors below 300 ppm, there was little accumulation since the uptake was rate limiting. The bioaccumulation factor body:air at steady state (K'st*) was rather low in comparison to the thermodynamic partition coefficient body:air (Keq) which was determined to be 420. K'st* increased from 2.7 at 10 ppm to 13 at 310 ppm in the rat and from 5.9 at 20 ppm to 13 at 310 ppm in the mouse. Above 300 ppm, K'st* increased considerably with increasing concentration since metabolism became saturated in both species. At levels above 2000 ppm K'st* reached its maximum of 420 being equivalent to Keq. Pretreatment with diethyldithiocarbamate, administered intraperitoneally (200 mg/kg in rats, 400 mg/kg in mice) 15 min prior to exposure of styrene vapours, resulted in effective inhibition of styrene metabolism, indicating that most of the styrene is metabolized by cytochrome P450-dependent monooxygenases.(ABSTRACT TRUNCATED AT 400 WORDS)

A pharmacokinetic model to describe toxicokinetic interactions between 1,3-butadiene and styrene in rats: predictions for human exposure.

Co-exposure to vapours of 1,3-butadiene and styrene occurs in the styrene-butadiene polymer manufacturing industry. Both compounds are biotransformed during a first step by cytochrome P450-dependent mono-oxygenases to epoxides--intermediates which are proven carcinogens. In a previous publication, we reported that metabolism of butadiene in rats was inhibited by simultaneous exposure to styrene, whereas butadiene had no effect on the kinetics of styrene. In order to translate these results into conditions of human exposure, we developed a physiologically based pharmacokinetic (PBPK) model, which is presented here. Maximal metabolic rates (Vmax) and Ostwald's partition coefficients were obtained using liver microsomes and tissues from rat and man. Apparent Michaelis (Km) and inhibition (Ki) constants were derived from previously published data on rats and were considered to be species-independent. The model was used to simulate human exposure to atmospheric mixtures of 5 and 15 ppm butadiene with 0.20 and 50 ppm styrene. It predicts that the presence of styrene significantly inhibits butadiene metabolism in man: At exposures up to 15 ppm, the amounts of butadiene metabolized can be expected to be reduced to 81 and 63% with co-exposure to styrene at 20 and 50 ppm, respectively.

Enzyme specific kinetics of 1,2-epoxybutene-3 in microsomes and cytosol from livers of mouse, rat, and man.

Kinetics of the metabolism of 1,2-epoxybutene-3 (butadiene monoxide) were investigated in liver fractions of mouse, rat, and man. In these species similar enzyme characteristics were found. In microsomes, no NADPH-dependent metabolism of butadiene monoxide was detectable. Epoxide hydrolase activity was found only in microsomes. The Vmax [nmol butadiene monoxide/(mg protein x min)] was 19 in mouse, 17 in rat, and 14 in man and the apparent Km (mmol butadiene monoxide/l incubate) was 1.5 in mouse. 0.7 in rat, and 0.5 in man. Glutathione S-transferase activity was found in cytosol only, revealing first order kinetics in the measured range. The ratio Vmax/Km [(nmol butadiene monoxide x 1)/(mg protein x min x mmol of butadiene monoxide)] was 15 in mouse, 11 in rat, and 8 in man. The data obtained were used to extrapolate on the total rate of butadiene monoxide metabolism for each species in vivo: it was calculated to be 1.3 times higher in mice and 2.3 times lower in man compared to rats, when corrected for body weight.