RESUMEN
Studies demonstrate that with sufficient dose and duration, 1,4-dioxane (1,4-DX) induces liver tumors in laboratory rodent models. The available evidence aligns with a threshold-dependent, tumor promotion mode of action (MOA). The MOA and key events (KE) in rats are well developed but less so in the mouse. Therefore, we conducted a 90-day drinking water study in female mice to evaluate early KE at 7, 28, and 90 days. Female B6D2F1/Crl mice consumed drinking water containing 0, 40, 200, 600, 2000 or 6000 ppm 1,4-DX. 1,4-DX was detected in blood at 90-days of exposure to 6000 ppm, but not in the other exposure groups, indicating a metabolic clearance threshold between 2000 and 6000. Early events identified in this study include glycogen-like vacuolization, centrilobular hypertrophy, centrilobular GST-P staining, apoptosis, and pan-lobular increase in cell proliferation observed after 90-days of exposure to 6000 ppm 1,4-DX. There was minimal evidence of hepatotoxicity over the duration of this study. These findings demonstrate a previously unreported direct mitogenic response following exposures exceeding the metabolic clearance threshold of 1,4-DX. Collectively, the information generated in this study supports a threshold MOA for the development of liver tumors in mice after exposure to 1,4-DX.
Asunto(s)
Carcinógenos/toxicidad , Dioxanos/toxicidad , Neoplasias Hepáticas/inducido químicamente , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/patología , Carcinógenos/farmacocinética , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dioxanos/sangre , Dioxanos/farmacocinética , Relación Dosis-Respuesta a Droga , Agua Potable , Femenino , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas/patología , Ratones , Pruebas de Toxicidad SubcrónicaRESUMEN
The present study investigated the toxicokinetics of 1,4-dioxane in humans exposed at rest and during physical stress. Eighteen volunteers were divided into three groups of six individuals each, who were exposed separately in three experiments to 20 ppm (73 mg/m(3)) 1,4-dioxane for 8 h. The first group was exposed at rest (Experiment 1), whereas the other groups performed exercises on a bicycle ergometer for 10 min every hour, corresponding to a physical exercise of 50 W (Experiment 2) and 75 W (Experiment 3), respectively. Blood samples were collected after 4 and 8 h, and all urine samples were collected over 24 h. The samples were analysed for 1,4-dioxane and its metabolite 2-(2-hydroxyethoxy)acetic acid (HEAA). The amount of urinary-eliminated HEAA increased during exposure and showed its maximum 9.8 ± 1.9 h after the beginning of exposure. The levels of 1,4-dioxane in blood and urine, however, barely rose above the limit of detection. Depending on the physical stress of the volunteers, the maximum elimination rate of HEAA in urine was significantly increased with 23.2 ± 7.7, 30.4 ± 7.2 and 41.8 ± 23.8 mg/h for Experiments 1, 2 and 3, respectively. Likewise, the cumulative HEAA excretion over 24 h increased with increasing physical stress; 53 ± 15 % of the theoretical inhaled 1,4-dioxane dose was excreted as HEAA in urine during the first 24 h. The average maximum level of HEAA ranged between 378 and 451 mg/g creatinine and increased with the applied physical stress. The half-life of HEAA was found to be 3.4 ± 0.5 h. Twenty-four hours after the beginning of the exposure, 31-51 mg HEAA/g creatinine were still detected in urine, indicating only a low accumulation of the metabolite during a working week. The study results revealed an increasing effect of the applied physical stress on the total eliminated amounts of HEAA as well as on the maximum HEAA levels at the end of exposure. For the estimation of biomonitoring equivalents to occupational exposure limits, this effect should be taken into account.
Asunto(s)
Dioxanos/farmacocinética , Dioxanos/toxicidad , Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Ejercicio Físico , Exposición por Inhalación/análisis , Simulación por Computador , Dioxanos/sangre , Dioxanos/orina , Contaminantes Ambientales/sangre , Contaminantes Ambientales/orina , Prueba de Esfuerzo , Voluntarios Sanos , Humanos , Límite de Detección , Tasa de Depuración Metabólica , Modelos Teóricos , Exposición Profesional/análisis , ToxicocinéticaRESUMEN
Six esterase inhibitors, namely EDTA·2Na(+), NaF, phenylmethanesulfonyl fluoride, dichlorvos, bis-nitrophenyl phosphate (BNPP) and thenoyltrifluoroacetone, and the mixture of NaF and BNPP, were evaluated for the stabilization of labile benzoate containing zeylenone in rat plasma. The mixture appeared to exhibit the most effectively stabilizing effect with the degraded content of zeylenone decreasing from >60% (in the absence of inhibitors) to <6%. Following the stabilization by the addition of NaF (5 mM) and BNPP (5 mM), the analytes in rat plasma were acidified by formic acid and extracted into ethyl acetate at 0°C. After chromatographic separation, the detection of zeylenone was performed on a 3200 Q-Trap with positive ion electrospray mode, monitoring the ion transition m/z 383.2 â 105.0. The method was validated over the range from 2.68 to 1340 ng/mL with inter- and intra-run precision for the quality control samples being less than 6.8%. The assay accuracy was within 100 ± 7.0%. The validated method was successfully applied to a pharmacokinetic study in rats after the intratracheal administration of zeylenone in free drug or polymeric micellar solutions. The results showed that the pulmonary absorption of zeylenone loaded in micelles was significantly retarded compared with that of free drug solutions.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ciclohexanos/sangre , Dioxanos/sangre , Inhibidores Enzimáticos/farmacología , Esterasas/antagonistas & inhibidores , Espectrometría de Masas en Tándem/métodos , Administración por Inhalación , Animales , Benzoatos/química , Ciclohexanos/administración & dosificación , Ciclohexanos/química , Ciclohexanos/farmacocinética , Dioxanos/administración & dosificación , Dioxanos/química , Dioxanos/farmacocinética , Estabilidad de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Masculino , Nitrofenoles/química , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Fluoruro de Sodio/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
There is a potential risk that 5-HT(1A) receptor blockade combined with blockade of the 5-HT transporter by an SSRI may cause a toxic increase in 5-HT within the synapse, sparking concern for 'serotonin syndrome', a rare but potentially life threatening condition. We evaluated the safety and pharmacodynamics of the combination of the 5-HT(1A) antagonist lecozotan and the SSRI citalopram in a well-controlled Clinical Pharmacology Unit setting using the Hunter Serotonin Toxicity Criteria (HSTC), a set of validated decision rules featuring neurological and body temperature measurements, to detect any clinically relevant serotonin toxicity. Forty-three young healthy male subjects were randomized, to 2 parallel double-blind treatment groups following a 10-day citalopram 40 mg run-in period: citalopram 40 mg/lecozotan 10mg or citalopram 40 mg/placebo for 9 days. Overall, the combined administration of active drugs was well tolerated, however, one subject experienced moderate hyperreflexia, tremor of the hands, and sweating of hands and feet after 3 days of combined treatment. The event prompted treatment withdrawal and was regarded as mild serotonin toxicity, as per the HSTC. The onset of the event was around the time of peak plasma concentrations (t(max)) of both lecozotan and citalopram, and its time course corresponds to the well-defined PK profile of lecozotan. No evidence of a PK interaction was detected trough lecozotan and citalopram plasma concentrations analysis. The utility of the HSTC in detecting the non-discrete group of symptoms commonly referred to as "serotonin toxicity" was demonstrated in this clinical pharmacology study combining two 5-HT agents in a clinically controlled setting.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Síndrome de la Serotonina/diagnóstico , Síndrome de la Serotonina/fisiopatología , Adulto , Citalopram/administración & dosificación , Citalopram/sangre , Estudios Cruzados , Dioxanos/administración & dosificación , Dioxanos/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Interacciones Farmacológicas , Electroencefalografía/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Piperazinas/administración & dosificación , Piperazinas/sangre , Antagonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Antagonistas del Receptor de Serotonina 5-HT1/sangre , Síndrome de la Serotonina/inducido químicamente , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The purpose of this open-label, parallel-group study was to investigate the effect of severe renal impairment on the pharmacokinetics (PK), tolerability, and safety of clazosentan, an intravenous endothelin receptor antagonist. Clazosentan was administered as a continuous intravenous infusion of 1 mg/h for a period of 6 hours in 9 subjects with severe renal impairment (group A) and 8 healthy subjects (group B) (creatinine clearance <30 mL/min and >80 mL/min, respectively). The subjects in both groups were well matched for sex, body mass index, and age (±10 years). The PK parameters of clazosentan were calculated by both model-independent and model-dependent methods. The differences in the PK parameters between the subjects with severe renal impairment and healthy subjects were minor. The geometric means for area under the curve (AUC) during the infusion, AUC(0-t), (AUC from zero to time t of the last measured concentration above the limit of quantification) AUC(0-∞) (AUC from zero to infinity), and concentration at steady state were 7%, 8%, 8%, and 8%, respectively, higher in group A than in group B. The results obtained after 2-compartmental modeling were in agreement with those obtained after noncompartmental analysis. Administration of clazosentan was well tolerated in both groups. The data suggest that there is no need for dose adjustment of clazosentan in patients with renal impairment.
Asunto(s)
Dioxanos/farmacocinética , Antagonistas de los Receptores de la Endotelina A , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Insuficiencia Renal/metabolismo , Sulfonamidas/farmacocinética , Tetrazoles/farmacocinética , Adulto , Dioxanos/administración & dosificación , Dioxanos/efectos adversos , Dioxanos/sangre , Femenino , Semivida , Humanos , Infusiones Intravenosas , Fallo Renal Crónico/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/sangre , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/sangre , Índice de Severidad de la Enfermedad , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/fisiopatología , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/sangre , Tetrazoles/administración & dosificación , Tetrazoles/efectos adversos , Tetrazoles/sangre , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/prevención & controlRESUMEN
OBJECTIVE: In this study, the distribution, metabolism and excretion of the endothelin receptor antagonist clazosentan were investigated. SUBJECTS AND METHODS: 4 healthy male subjects received an intravenous 3-h infusion at a rate of 0.2 mg/kg/h of 14C-labeled clazosentan and blood, urine and feces samples were collected for a period of 8 days. Experiments were performed to investigate the plasma protein binding, the binding to red blood cells and the inhibition potential of cytochrome P450 isoenzymes of clazosentan. RESULTS: Clazosentan was mainly excreted unchanged into feces whereas about 15% of the radioactive dose was recovered in urine. No metabolites representing more than 5% of total radioactivity were identified. No relevant inhibition of the human cytochrome P450 isoenzymes, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4, was observed in vitro at clazosentan concentrations largely exceeding those observed in clinical trials. In human blood, clazosentan was highly bound to plasma proteins and did hardly penetrate into red blood cells. CONCLUSION: The primary route of excretion of clazosentan was via the feces, mainly as unchanged drug.
Asunto(s)
Dioxanos/farmacocinética , Antagonistas de los Receptores de la Endotelina A , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Tetrazoles/farmacocinética , Adulto , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Dioxanos/sangre , Dioxanos/orina , Heces/química , Semivida , Humanos , Técnicas In Vitro , Infusiones Intravenosas , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Unión Proteica , Piridinas/sangre , Piridinas/orina , Pirimidinas/sangre , Pirimidinas/orina , Receptor de Endotelina A/metabolismo , Sulfonamidas/sangre , Sulfonamidas/orina , Tetrazoles/sangre , Tetrazoles/orina , Distribución TisularRESUMEN
Thirteen-week inhalation toxicity of 1,4-dioxane was examined by repeated inhalation exposure of male and female F344 rats to 0 (control), 100, 200, 400, 800, 1600, 3200, or 6400 ppm (v/v) 1,4-dioxane vapor for 6 h/day and 5 days/wk. All the 6400-ppm-exposed males and females died during the first week. Terminal body weight decreased, and relative weights of liver, kidney, and lung increased. AST increased in the 200 ppm-and 3200-ppm-exposed females, and ALT increased in the 3200-ppm-exposed males and females. Nuclear enlargement of nasal respiratory epithelial cells occurring in the 100-ppm-exposed males and females was the most sensitive, followed by the enlarged nuclei in the olfactory, tracheal, and bronchial epithelia. 1,4-Dioxane-induced liver lesions occurred at higher exposure concentrations than the nasal lesions did, and were characterized by single-cell necrosis and centrilobular swelling of hepatocytes in males and females. Glutathione S-transferase placental form (GST-P) positive liver foci were observed in the 1600-ppm-exposed females and 3200-ppm-exposed males and females, which are known as a preneoplastic lesion in rat hepatocarcinogenesis. Plasma levels of 1,4-dioxane increased linearly with an increase in the concentrations of exposure to 400 ppm and above. The enlarged nuclei in the nasal epithelia and the GST-P-positive liver foci were discussed in light of the possible development of nasal and hepatic tumors by long-term inhalation exposure to 1,4-dioxane. A lowest-observed-adverse-effect level (LOAEL) was determined at 100 ppm for the nasal endpoint in both male and female rats.
Asunto(s)
Dioxanos/toxicidad , Administración por Inhalación , Animales , Bronquios/efectos de los fármacos , Dioxanos/administración & dosificación , Dioxanos/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Hígado/efectos de los fármacos , Masculino , Cavidad Nasal/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Tráquea/efectos de los fármacosRESUMEN
Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT(4)) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT(4) receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT(4) receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT(4) receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [(123)I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT(4) receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT(4) receptor antagonist, SB 204070, at 20 min before [(123)I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [(123)I]SB 207710 is an effective radioligand for imaging brain 5-HT(4) receptors in vivo.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Dioxanos/farmacocinética , Radioisótopos de Yodo/farmacocinética , Piperidinas/farmacocinética , Receptores de Serotonina 5-HT4/metabolismo , Animales , Dioxanos/sangre , Radioisótopos de Yodo/sangre , Marcaje Isotópico/métodos , Ligandos , Macaca fascicularis , Masculino , Tasa de Depuración Metabólica , Piperidinas/sangre , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
Behavioral effects of 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-be nzodioxole HCl (MKC-242), a novel 5-HT1A-receptor agonist, were evaluated using animal models of anxiety and obsessive compulsive disorder and compared against reference compounds. MKC-242 suppressed foot shock-induced fighting behavior without loss of motor coordination in mice as the reference compounds did. The ED50 values of MKC-242, buspirone, tandospirone and diazepam were 1.7, 42, 80 and 2.0 mg/kg, p.o., respectively. The duration of the suppression of fighting by MKC-242 was longer than those of buspirone and tandospirone and comparable to that of diazepam. Similar results were also obtained with the water-lick conflict test in rats. The plasma concentration of MKC-242 in rats was much higher than the reported value of buspirone during 0.25-6 hr after oral administration. In addition, MKC-242 reduced marble burying behavior without reduction of motor activity. Fluoxetine, tandospirone and diazepam also reduced the behavior at non-sedative doses. These findings indicate that MKC-242 possesses a longer-lasting anxiolytic effect than azapirones. This might be due to the high concentration of the compound in plasma. In addition, it is also suggested that MKC-242 possesses an antiobsessional effect.
Asunto(s)
Agresión/efectos de los fármacos , Dioxanos/farmacología , Dioxoles/farmacología , Conducta Obsesiva/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Buspirona/farmacología , Diazepam/farmacología , Dioxanos/sangre , Dioxoles/sangre , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Isoindoles , Masculino , Ratones , Ratones Endogámicos ICR , Piperazinas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Wistar , Receptores de Serotonina 5-HT1RESUMEN
Sensitive and specific methods for the determination of efaroxan and idazoxan in blood plasma have been developed based on solvent extraction, chromatographic separation and quantification by selected-ion monitoring using a quadruple mass-selective detector. The use of a short non-polar bonded-phase capillary gas chromatography (GC) column facilitated rapid separation of the compounds of interest from internal standards, metabolites and endogenous material. Of equal significance was the ability to chromatograph these basic compounds without prior derivatisation. The application of bonded-phase capillary GC coupled to selected-ion monitoring resulted in robust analytical procedures with sub-ng ml(-1) sensitivity and high selectivity.
Asunto(s)
Antagonistas Adrenérgicos alfa/sangre , Benzofuranos/sangre , Dioxanos/sangre , Dioxinas/sangre , Imidazoles/sangre , Cromatografía de Gases y Espectrometría de Masas , Humanos , IdazoxanRESUMEN
l-3-[(Dimethylamino)-(m-dioxan-5-yl)methyl]pyridine hydrochloride (LY 108380) is being evaluated in man as a potentially useful, nonaddicting analgesic agent. This substituted dioxane is structurally different from any currently known analgesic. Following im administration of the 14C-labeled compound to healthy volunteers, the drug was absorbed rapidly (t1/2(abs) = 2--20 min). Pharmacokinetic analyses suggested that LY 108380 was widely distributed and extensively bound in tissues. The drug was not bound to plasma proteins in vitro or in vivo. In the blood, radioactivity was distributed in both red cells and plasma; a cell/plasma radioactivity ratio of 0.5 was maintained for about 1 hr. The t1/2 for elimination of LY 108380-14C from plasma was about 1.3 hr, although radioactivity persisted in plasma for over 100 hr. At the time of peak radioactivity, the parent compound was the major constituent in plasma; quaternary N-glucuronide and N-desmethylated metabolites were also detected in plasma. Levels of radioactivity in saliva were 2--5 times higher than those in plasma shortly after drug administration. About 82% of the radioactivity was eliminated in the urine, 6% in expired air (as 14CO2), and 1% in feces. The major metabolite of LY 108380 (55% of the dose) was a quaternary amine formed by glucuronidation at the pyridine nitrogen. Less than 10% of the dose was N-demethylated to secondary and primary amines, and about 2% was excreted unchanged.
Asunto(s)
Dioxanos/metabolismo , Dioxinas/metabolismo , Piridinas/metabolismo , Adulto , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Dioxanos/sangre , Heces/análisis , Glucuronatos/análisis , Humanos , Masculino , Espectrometría de Masas , Unión Proteica , Piridinas/sangre , Saliva/análisisRESUMEN
Toxic parameters of 1-4 dioxan were estimated to be for white rats during 4 hr inhalation LC16 = 40 mg/l LC50 = 46 (42.2 +/- 50.1) mg/l; LC84 = 52 mg/l; for white mice during 2 hr inhalation LC16 = 61 mg/l; LC50 = 65 (61.3 +/- 68.2) mg/l; LC84 = 69.5 mg/l. As a result of single and repeated application, 1-4 dioxan did not induce skin changes, it was rapidly absorbed into the blood, and led to acute poisoning and irritation of the eye mucosa. A 24 hr exposure of white rats to 1-4 dioxan at concentrations of 4 and 20 mg/m3 for 90 days brought about their delayed weight gain, increased activity of glutamate-aspartate and glutamate-alanine transminases, prolonged duration of narcotic sleep, elevated content of protein in the urine, decreased diuresis, changed content of chlorides and altered motor chronaxia. The above concentrations proved to be effective. 1-4 dioxan at a concentrations proved to be effective. 1-4 dioxan at a concentration of 0.5 mg/m3 produced slight threshold changes.
Asunto(s)
Dioxanos/toxicidad , Dioxinas/toxicidad , Animales , Conjuntiva/efectos de los fármacos , Dioxanos/sangre , Relación Dosis-Respuesta a Droga , Exposición a Riesgos Ambientales , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Ratones , Conejos , Ratas , Absorción Cutánea/efectos de los fármacos , Factores de TiempoRESUMEN
1,4-Dioxan and its principle metabolite, beta-hydroxyethoxyacetic acid (HEAA), are determined by gas chromatography-mass spectrometry (GC-MS) on a 3% OV-17 column using selected ion monitoring, following the methylation of HEAA directly in plasma or urine without extraction. The recoveries of dioxan from plasma and urine are 98 and 94%, respectively, and the recoveries of HEAA from plasma and urine are 86 and 94%, respectively. The detection limits of 1,4-dioxan in plasma and urine are 0.07 ppm, and the detection limits of HEAA in plasma and urine are 0.5 and 0.1 ppm, respectively. Separate simultaneous measurements of 1,4-dioxan and HEAA methyl ester concentrations in urine and plasma are obtained after the methylation via GC-MS without additional preparation of the samples.