Tamie Nakajima

Partition coefficients of some aromatic hydrocarbons and ketones in water, blood and oil.

Water/air, blood/air, oil/air, oil/water, and oil/blood partition (or solubility) coefficients of 17 aromatic hydrocarbons and ketones were measured by a newly developed vial-equilibration method, which needs no direct measurements of the concentration either in the liquid or in the air phase, but only the gas chromatographic peak heights of the air in the sample (in which a test material is contained) and reference vessels (containing no test material). It was found that the blood/air partition coefficients for aromatic hydrocarbons are correlated closely with the product of water/air and oil/air partitiion coefficients, whereas those for ketones are almost in the same range as the water/air, irrespective of the oil/air partition coefficients.

Sarin poisoning in Matsumoto, Japan

A presumed terrorist attack with sarin occurred in a residential area of the city of Matsumoto, Japan, on June 27, 1994. About 600 residents and rescue staff were poisoned; 58 were admitted to hospitals, and 7 died. We examined clinical and laboratory findings of 264 people who sought treatment and the results of health examinations on 155 residents done 3 weeks after the poisoning. Findings for severely poisoned people were decreases in serum cholinesterase, acetylcholinesterase in erythrocytes, serum triglyceride, serum potassium and chloride; and increases in serum creatine kinase, leucocytes, and ketones in urine. Slight fever and epileptiform abnormalities on electroencephalogram were present for up to 30 days. Examination revealed no persisting abnormal physical findings in any individual. Acetylcholinesterase returned to normal within 3 months in all people examined. Although subclinical miosis and neuropathy were present 30 days after exposure, almost all symptoms of sarin exposure disappeared rapidly and left no sequelae in most people.

Sarin experiences in Japan: acute toxicity and long-term effects

Two terrorist attacks with the nerve agent Sarin affected citizens in Matsumoto and Tokyo, Japan in 1994 and 1995, killing 19 and injuring more the 6000. Sarin, a very potent organophosphate nerve agent, inhibits acetylcholinesterase (AchE) activity within the central, peripheral, and autonomic nervous systems. Acute and long-term Sarin effects upon humans were well documented in these two events. Sarin gas inhalation caused instantaneous death by respiratory arrest in 4 victims in Matsumoto. In Tokyo, two died in station yards and another ten victims died in hospitals within a few hours to 3 months after poisoning. Six victims with serum ChE below 20% of the lowest normal were resuscitated from cardiopulmonary arrest (CPA) or coma with generalized convulsion. Five recovered completely and one remained in vegetative state due to anoxic brain damage. EEG abnormalities persisted for up to 5 years. Miosis and copious secretions from the respiratory and GI tracts (muscarinic effects) were common in severely to slightly affected victims. Weakness and twitches of muscles (nicotinic effects) appeared in severely affected victims. Neuropathy and ataxia were observed in small number (less than 10%) of victims, which findings disappeared between 3 days and 3 months. Leukocytosis and high serum CK levels were common. Hyperglycemia, ketonuria, low serum triglyceride, hypopotassemia were observed in severely affected victims, which abnormalities were attributed to damage of the adrenal medulla. Oximes, atropine sulphate, diazepam and ample intravenous infusion were effective treatments. Pralidoxime iodide IV reversed cholinesterase and symptoms quickly even if administered 6 h after exposure. Post Traumatic Stress Disorder (PTSD) was less than 8% after 5 years. However, psychological symptoms continue in victims of both incidents. In summary, both potent toxicity and quick recovery from critical ill conditions were prominent features. Conventional therapies proved effective in Sarin incidents in Japan.

Bisphenol A may cause testosterone reduction by adversely affecting both testis and pituitary systems similar to estradiol.

Bisphenol A (BPA) causes reproductive toxicities, but the mechanisms are still unclear. In the present study, we sought to clarify these mechanisms in comparison with those of 17beta-estradiol (E2). Prepubertal Wistar/ST male rats (4 weeks old) were subcutaneously administered BPA (0, 20, 100 and 200 mg/kg/day) or E2 (10 and 100 microg/kg/day) for 6 weeks. Both BPA and E2 treatments decreased plasma and testicular testosterone levels, and plasma luteinizing hormone (LH), but not E2 and follicle-stimulating hormone levels, though E2 treatment increased its plasma level. In relation to the decreased testosterone levels, BPA and E2 decreased expressions of steroidogenic enzymes and cholesterol carrier protein in Leydig cells. Thus, decreased testosterone levels in plasma might have resulted from decreased expressions of these enzymes and protein as well as from decreased plasma LH levels. Interestingly, the changes in steroidogenic enzymes and carrier protein were observed at lower levels of exposure to BPA or E2 than those inhibiting plasma LH levels. Microscopically, 200 mg/kg BPA and 100 microg/kg E2 significantly decreased Leydig cell numbers in the testis. In addition, BPA and E2 also decreased expression of estrogen receptor alpha-mRNA, which might be related to the decreased numbers of Leydig cells. Thus, BPA directly affects not only the Leydig cells but also the pituitary gland, but the former may be impaired at lower exposure concentrations than the latter.

A vial-equilibration method to evaluate the drug-metabolizing enzyme activity for volatile hydrocarbons

Abstract A simple but sensitive vial-equilibration technique to evaluate liver microsomal enzyme activity for volatile hydrocarbons is described. The substrate, toluene or trichloroethylene ( q mol), is incubated together with the mixture of enzyme and cofactor in a small airtight closed vial for a period of time ( t ). No direct determination of the product formed or of the substrate disappeared is necessary; only the ratio of gas chromatographic peak height ( h ′) obtained from the air phase in the sample vial (intact enzyme is used) to that ( h ) from the reference vial (inactivated enzyme is used) is needed to calculate the rate of enzymatic reaction ( v ), i.e., v = q (1− h ′/ h )/ t . The time-activity and enzyme-activity studies proved the method to be useful for the evaluation of enzyme activity.

Di(2-ethylhexyl)phthalate Induces Hepatic Tumorigenesis through a Peroxisome Proliferator-activated Receptor α-independent Pathway

Di(2‐ethylhexyl)phthalate Induces Hepatic Tumorigenesis through a Peroxisome Proliferator‐activated Receptor α‐independent Pathway: Yuki Ito, et al. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine—Di(2ethylhexyl)phthalate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator‐activated receptor alpha (PPARα). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPARα, we compared DEHP‐induced tumorigenesis in wild‐type and Pparα‐null mice. Mice of each genotype were divided into three groups, and treated for 22 months with diets containing 0, 0.01 or 0.05% DEHP. Surprisingly, the incidence of liver tumors was higher in Pparα‐null mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild‐type mice (10.0%). These results suggest the existence of pathways for DEHP‐induced hepatic tumorigenesis that are independent of PPARα. The levels of 8‐OHdG increased dose‐dependently in mice of both genotypes, but the degree of increase was higher in Pparα‐null than in wild‐type mice. NFκB levels also significantly increased in a dose‐dependent manner in Pparα‐null mice. The protooncogene c‐jun‐mRNA was induced, and c‐fos‐mRNA tended to be induced only in Pparα‐null mice fed a 0.05% DEHP‐containing diet. These results suggest that increases in oxidative stress induced by DEHP exposure may lead to the induction of inflammation and/or the expression of protooncogenes, resulting in a high incidence of tumorigenesis in Pparα‐null mice.

Dose-dependent metabolic interaction between benzene and toluene in vivo and in vitro

Abstract When benzene or toluene was administered to rats ip in combination with the other, their disappearance rate from blood and the rate of urinary excretion of their metabolites were delayed compared with those when they were given separately. This metabolic interaction was found to be dose dependent. The metabolism of benzene or toluene studied in vitro with rat liver 10,000g supernatant fraction was inhibited competitively by the presence of the other. The solubility of benzene and toluene in blood and their binding with bovine serum albumin were not influenced by the presence of the other, indicating that absorption and distribution are unaffected by their simultaneous presence. A human experimental exposure to a mixture of benzene and toluene revealed that there is no significant interaction between them with respect to their fate when exposure is near the threshold limit value.

Cytochrome P450 isozymes responsible for the metabolism of toluene and styrene in human liver microsomes

1. Cytochrome P450 isozymes from Asian (31 Chinese subjects) and Caucasian (14 Finnish subjects) livers were examined for their roles in the metabolism of toluene (rates of benzyl alcohol, o- and p-cresol formation) and styrene (rates of styrene glycol formation). 2. For toluene, the overall rate of metabolism was higher in samples from Finnish than from Chinese subjects. At 0-20 mM toluene, the rate of o-cresol formation was significantly higher in Finnish microsomes than in Chinese ones. The formation rates of benzyl alcohol and p-cresol in Finnish samples were also higher than those of Chinese samples, but only at a high substrate concentration (5.0 mM). For styrene metabolism, the Chinese liver microsomes showed higher metabolic rates than the Finnish ones at 0.085 mM styrene, but not at the higher substrate concentration. 3. Mean expression levels of immunochemically detected CYP1A2/1 and CYP2B6 were almost 3-fold higher in Finnish microsomes, whereas CYP2E1 was 1.7-fold higher in Chinese samples. 4. Correlation analysis showed that CYP2E1 (benzyl alcohol formation) and CYP1A2/1 (o-cresol formation) contributed to the metabolism of toluene at the low substrate concentration, whereas CYP2C8 was the form more actively involved at the higher toluene concentrations. At the higher concentration (1.8 mM) of styrene, CYP2B6 was most active isozyme to catalyse the formation of styrene oxide from styrene. 5. These results suggest that CYP2E1 and CYP1A2/1 are the main isoforms responsible for the metabolism of toluene at low substrate concentrations in human liver microsomes, CYP2E1 at low styrene concentration, and CYP2C8 and CYP2B6 at high concentrations of toluene and styrene respectively.

Pharmacokinetics of benzene and toluene

Summary1.Experimental human exposure of benzene and toluene: Elimination curves obtained from a single exposure in which three male subjects inhaled 25 ppm of benzene and 100 ppm of toluene for 2 hrs were graphically resolved into a sum of three exponential components; for benzene in blood,