Recently many studies on the health effects of workers who exposed to low-concentration styrene have been published. In this paper firstly we mentioned the reasons why nervous system was critical organ for evaluating the toxicity of organic solvents both in the acute and chronic exposure phases. Then we indicated how neurobehavioral test batteries were useful to detect subclinical adverse health effects of workers exposed to organic solvents. Secondly we reviewed many epidemiological studies on the impairment of neurobehavioral function, i.e., perceptual speed, memory, cognition, personality and mood, and the loss of color vision among styrene workers. Finally, we showed our recent data on the relationship between color vision loss and the concentration of urine metabolites among styrene workers. It can conclude that styrene may cause damage on nervous system, even at the low exposure level such as 50 ppm which used to be the Threshold Limit Value (TLV) recommended by Japan Society for Occupational Health (until 1999) and American Conference of Industrial Hygienists (until 1997).
Biomarkers of exposure, effect, and susceptibility are reviewed in relation to lead exposure. Of the biomarkers of lead exposure, blood lead (Pb-B), mainly red cell lead, is a representative of soft tissue lead, and most widely used as measures of body burden and absorbed (internal) doses of lead. Urine lead (Pb-U) as well as plasma lead (Pb-P) increases exponentially with increasing Pb-B under a steady-state situation and is a reflection of recent exposure. The amount of lead in plasma and urine (MPb-P and MPb-U) after administration of a chelating agent (e.g CaEDTA) can be useful for biomarkers of internal exposure of lead, reflecting the mobilizable pool of lead which consists of mainly blood and soft tissue lead with only a small fraction derived from bones. The critical effects in bone marrow arise mainly from the interaction of lead with some enzymatic process responsible for heme synthesis. The effects can be used for the biomarkers of effects. They are the inhibition of delta-aminolevulinic acid dehydratase (ALAD) and the variation in some metabolite concentrations (e.g. delta-aminolevulinic acid in urine (ALA-U), blood (ALA-B) or plasma (ALA-P), coproporphyrin in urine (CP), zinc protoporphyrin (ZP) in blood). The activities of pyrimidine nucleotidase (P5'N) and nicotinamide adenine dinucleotide synthetase (NADS) in blood are also decreased in lead exposure, and nucleotide contents in blood is altered in lead exposure. These effects of lead on human can be also useful biomarkers of effect. The differences in levels of heme precursors between two types of ALAD genotypes might be attributable to those in the affinity of different ALAD isozymes to lead. ALAD1 homozygotes have higher levels of ZP and ALA in comparison with ALAD2 carriers at the high lead exposure, suggesting that ALAD1 homozygotes might be more susceptible for disturbance in heme biosynthesis by lead than ALAD2 carriers.
Polymorphism and the induction/inhibition of drug-metabolizing enzymes, such as cytochrome P450, aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), Nacetyltransferase (NAT), and NAD(P)H-quinone oxidoreductase (NQO1), were reviewed in relation to susceptibility to disease and to inter-individual difference in biological monitorings. A number of genetic and acquired factors can influence the susceptibility of an individual to chemicals, creating a so-called predisposition. Most cases in which genetic factors were present resulted from polymorphism of drug-metabolizing enzymes. However, conflicting reports have appeared on the relationship between polymorphism and risk of disease; in some cases, biologically plausible mechanisms linking genotypes and disease are not yet in evidence. Current findings based on biological monitoring of chemicals are insufficient to evaluate the relationship between genetic polymorphism and acquired risk when exposure has occurred in an occupational area. Investigation of such situations has generated data implicating GSTT1, GSTM1, NAT2, and NQO1 polymorphisms in biological monitoring of some chemicals; the ALDH2 polymorphism is the likely link between the genotype and the metabolism of low molecular aliphatic aldehydes. Although this polymorphism is limited in the case of Japanese as well as other Asian subjects, the inhibitors of ALDH2 activity such as trichloroethylene may produce a false polymorphism of this gene. As to the effect of factors influencing acquired predisposition, such as ethanol intake, intake of low carbohydrate diet or diabetes, corroborative epidemiological studies may be further required.
Mercury exists in various chemical forms. The important forms from a toxicological viewpoint are the metallic form, also called the elemental form, the divalent inorganic forms and methylmercury compounds. Elemental (Hg0) mercury has a high vapor pressure and the vapor causes a number of cases of poisoning via inhalation. Classical mercury poisoning is characterized by a triad of signs, namely tremors, erethism and gingivitis. Mercurial erethism, which is characterized by behavioral and personality changes such as extreme shyness, excitability, loss of memory, and insomnia are also observed. Recently, the effects of mercury exposure at levels around 0.05 mg/m3 or lower have been of concern and may include minor renal tubular damage, increased complaints of tiredness, memory disturbance and other symptoms, subclinical finger tremor, abnormal EEG by computerized analysis and impaired performance in neurobehavioral or neuropsychological tests. Abnormal gait, dysarthria, ataxia, deafness and constriction of the visual field are typical of the symptoms of methylmercury poisoning observed in Minamata and Iraqi outbreaks, as well as in occupational methylmercury poisoning cases. Furthermore, an infant born to a mother with excessive methylmercury consumption showed various neurological disturbances and delayed development. Since several populations are believed to be still exposed to methylmercury through the consumption of fish and sea mammals, neurobehavioral deviations in children of these populations have recently been investigated.
The occupational exposure limit for acrylonitrile (AN) has been set by many organizations on the basis of its carcinogenicity. However, recent epidemiological studies do not afford evidence supporting the hypothesis that AN is carcinogenic to humans. Review of the 18 published cohort studies revealed that, although there is not adequate evidence in humans for carcinogenicity of AN, the possibility of a causal association between high exposure to AN and lung cancer in humans cannot be excluded. It was pointed out that carcinogenic potential of AN may be weak, if any, to humans, and the current occupational exposure limit (OEL) for AN of 2 ppm was evaluated as appropriate in view of AN exposure levels reported by epidemiological studies. Based also on review of the literature on health effects other than carcinogenicity, it was concluded that the current OEL for AN is a reasonable value and there is no need for a revision at present.
The present study was initiated to examine the quantitative relationship between bloodlead (Pb-B) and urinary δ-aminolevulinic acid (ALA-U) among Pb-exposed workers, and to find a threshold Pb-B level to induce an increase in ALA-U. For this purpose, pairs of venous blood and spot urine samples were collected from 8, 274 men and 5, 856 women (14, 130 workers in total) who were occupationally exposed to inorganic lead. The blood and urine samples were analyzed for Pb-B and ALA-U by atomic absorption spectrometry and colorimetry, respectively, and the correlation between pairs of measures were subjected to statistical analysis. The assumption of the 3rd degree regression for correlation gave a substantially greater correlation coefficient (0.645 for men and 0.619 for women) than 1st or 2nd degree regression, whereas only very small improvement in the coefficient was achieved with 4th to 6th degree ones. Logarithmic conversion of the parameters was not effective in improving the correlation. The assumption of the 3rd degree regression followed by calculation of the local minimum gave 22, 29 and 23 μg/100ml Pb-B for men, women, andmen+women, respectively, as the threshold Pb-B to induce ALA-U increase. Pb-B to elevate ALA-U to the 95% upper normal limit (8 mg/l, common to men and women) was 62, 50 and 58 μg/100ml for men, women and men+women, respectively. The validity of the 3rd degree regression assumption as a tool to calculate a threshold from experimental or epidemiological data is discussed.
To examine the effects of 2, 5-hexanedione (HD) on the glucose metabolism in the spinal cord, glucose utilization rate (GUR) and distribution volume of glucose (DV) were measured in the white matter and anterior horn of the spinal cord in 8 rats exposed to HD for 4 weeks and in 10 control rats. The GUR and DV were determined by the quantitative microdetermination method using non-tracer 2-deoxyglucose based on the three-compartments model of Sokoloff. GURs in the white matter and anterior horn and DV in the anterior horn in the HD-exposed rats were significantly lower than those in the control rats. In the multiple regression analysis, GUR in the white matter of HD-exposed rats was significantly related to blood HD concentration. It is suggested that the decrease of GUR in the white matter is a major effect of HD in the spinal cord.
A hand-saving HPLC method to measure urinary phenylmercapturic acid (PMA) was developed which allows about 35 PMA determinations per day. The method involves conversion of pre-PMA to PMA by the addition of sulfuric acid to a urine sample, extraction into an ether-methanol mixture followed by condensation under a nitrogen stream. The condensate was introduced to a ODS-3 column in a HPLC system, and PMA in the column was eluted into a mobile phase of acetonitrile: methanol: perchloric acid: water. The elution of PMA was monitored at 205 nm. One determination will be completed in 40 min. The method was applied to analysis of end-of-shift urine samples from 152 workers exposed up to 210 ppm benzene, 66 workers exposed to a mixture of benzene (up to 116 ppm) and toluene+xylenes (up to 118 ppm), and 131 non-exposed controls of both sexes. A linear regression was established between time-weighted average intensity of exposure to benzene and urinary PMA. From the regression, it was calculated that urinary PMA level will be about 6.4 mg/l after 8-hour exposure to benzene at 100 ppm, and that PMA in urine accounted for about 0.1% of benzene absorbed. No effects of sex, age, and smoking habit of individuals were detected, and the effect of co-exposure to toluene + xylenes at the levels comparable to that of benzene was essentially nil, which indicates an advantage of PMA as a benzene exposure marker over monoto tri-phenolic metabolites or t, t-muconic acid.
To elucidate circadian rhythms (variation within a day) of 7 toxic or essential metals in plasma and erythrocytes in relation to the rhythms in urine in men, 19 male metal foundry workers were examined; they were exposed to lead (Pb), zinc (Zn) and copper (Cu) occupationally but separated from the exposure during the study. Circadian rhythms were found for plasma concentration of Pb, cadmium (Cd), Zn, Cu and chromium (Cr) in the workers. Circadian rhythms were also found for Pb, inorganic mercury (Hg), Zn and Cr in erythrocytes and for all metals except Zn in urine. Both the plasma and urinary levels of Pb, Cd, Cu and Cr together with urinary excretion of Mn and creatinine tended to decrease during night hours; both the erythrocyte and urinary levels of Hg together with both the plasma and erythrocyte levels of Zn tended to increase during morning hours. The results of profile analysis suggested that the circadian rhythm of Pb in urine was affected more strongly by its plasma and erythrocyte rhythms than by the rhythm of creatinine in urine, i.e. the rhythm of glomerular filtration; the urinary rhythms of Cd, Cr, and Mn were affected more by the creatinine rhythm; and the urinary rhythm of Cu was affected by both its plasma and creatinine rhythms. On the other hand, the urinary rhythm of Hg was assumed to be independent of the creatinine rhythm and be affected by its erythrocyte rhythm. The present study suggested that different biological limit values might be needed for different hours of the day especially for shift workers who are exposed to various heavy metals. Instead, further studies should be conducted to find the adjustment methods by which no circadian rhythms are discerned.
Possible induction of lacZ mutation was examined in the liver and testis of Muta™Mouse following the administration of carcinogenic halogenated compounds, namely 1, 2-dichloroethane (DCE), 1, 2-dibromoethane (DBE), carbon tetrachloride, or 1, 2-dibromo-3-chloropropane (DBCP). Slight increases were observed on the mutant frequency in the testis DNA isolated from the mice 14 days after treatment with DBCP at 40 mg/kg or with DBE at 60 mg/kg but not in the liver. Further investigation was necessary to confirm the mutation induction by these chemicals in the testis including experiments with longer sampling intervals. No increase was detected in the frequency following DCE administration of single doses of up to 150 mg/kg or of consecutive injections of up to 280 mg/kg. Marginal but biologically insignificant responses were observed in the liver from the carbon tetrachloride exposed mice. The present results suggest that these carcinogenic chemicals are less efficient for induction of gene mutation in the liver of Muta™Mouse.
To examine the effects of lead on glucose metabolism in the spinal cord, glucose utilization rate (GUR) and distribution volume of glucose (DV) in the anterior horn and white matter were determined in 9 rats exposed to lead for 4 weeks and 10 control rats. The GUR and DV were determined by the quantitative microdetermination method using non-tracer amount of 2-deoxyglucose based on the three-compartments model of Sokoloff. The GUR and DV in the anterior horn in the lead-exposed rats were significantly lower than those in the controls. It is thus suggested that glucose metabolism, as measured by the GUR and DV, in the anterior horn is inhibited by lead; the anterior horn cells seem sensitive to lead neurotoxicity.
Heavy metals are expected to affect the biological activity of various metal-containing proteins, including transcriptional regulators. We studied the effects of several heavy metal ions on the DNA-binding activity of a Zn-finger transcription factor, Sp1. With respect to both DNA elements through which Sp1 acts positively and negatively, Cd2+inhibited DNA-binding of Sp1 at 20 μM or higher, while the toxic effect of Zn2+ was obvious only at more than 200 μM. Inhibition was also apparent for Cu2+ but less remarkable for Hg2+. The inhibition by Cd2+ was relieved by the additionof Zn2+ at much lower concentrations than that of Cd2+. These results suggest that the toxic potential of heavy metals could be largely influenced by the intracellular Zn2+ concentration.
To determine the potentially lethal level of thinner concentration in the air, we measured the concentration of toluene in the blood and others of three patients who suffered severe acute thinner intoxication between 4 January 1996 and 21 April 1997 in Ube city. The concentration of toluene in blood were 30.2mg/L in died patient, and 13.7mg/L and 17.5mg/L in recovered patients, respectively. By extrapolation from the results of our previous toxicokinetic reseach on toluene poisoning in anesthetized dogs, the fatal concentration of toluene was estimated to be approximately 1800 to 2000 ppm for 1-hour exposure.
We examined the effect of body weight change on the modification of atherogenic risk factors in 296 middle-aged obese male office workers without medication for hypertension, dyslipidemia, hyperuricemia or diabetes mellitus. During a 1-year education program, 39.2% of the participants could reduce their weight, and the percentage of those who lost 2 kg or more was only 17.7%. Concomitant with the decrease of weight, however, the levels of systolic and diastolic blood pressures, total cholesterol, triglyceride, uric acid and hemoglobin 1c and the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol decreased significantly, whereas the HDL cholesterol level increased significantly. In a multivariate regression analysis, in addition to the initial risk-factor level, weight change was an important factor determining the changes in atherogenic risk factors. Changes in alcohol consumption were significantly associated with the changes in systolic blood pressure and HDL cholesterol levels. Changes in cigarettes smoking also showed significant associations with the changes in triglyceride level and the ratio of total cholesterol to HDL cholesterol. These results suggest that although the education program for controlling weight may have limited success, weight reduction exhibits beneficial changes in the atherogenic risk-factor profile in middle-aged obese men.
Alveolar macrophages are thought to play an important role in fibrogenesis in the lungs caused by various types of exposure to dust. In this experiment, we evaluated the effect of silicon carbide whiskers (SiC) on alveolar macrophages mainly by unique magnetometry and also by established methods such as lactate dehydrogenase (LDH) activity, apoptosis measurement and morphological observations. Alveolar macrophages obtained from Syrian golden hamsters by bronchoalveolar lavages were exposed in vitro to Fe3O4 for 18 hours as an indicator for magnetometry and SiC for experiments. A rapid decrease of the remanent magnetic field, so called “relaxation”. was observed after cessation of an external magnetic field in macrophages phagocytizing Fe3O4 alone, while relaxation was delayed in those concurrently exposed to SiC. Release of LDH from SiCexposed macrophages into the medium was not significantly higher than the controls, but it increased dose-dependently. Apoptosis was recognized in macrophages exposed to 60μg/ml of SiC by the DNA ladder detection method and morphological observations. Electron microscopic examination revealed irregular forms of nuclei and organellas in macrophages exposed to SiC. Magnetometry, LDH release and electron microscopic observation indicated mild cytotoxicity of SiC to alveolar macrophages.
To clarify whether job stressors affecting injury due to labor accidents differ between Japanese male and female blue-collar workers, the Job Content Questionnaire (JCQ), assessing dimensions of job stressors based on the demand-control-support model, was applied to 139 bluecollar workers in a manufacturing factory. Of them, 24 male and 15 female workers suffered from injuries at work. In the female workers with the experience of work injury, the job demand score and job strain index (i.e., the ratio of job demand to job control) of the JCQ were significantly higher and the score of coworker support was significantly lower, than those in the female workers without the experience. High job demand (or, high job strain and low coworker support) was significantly related to work injury in all the female workers. Between the male workers with and without work injury, however, there was no significant difference in any job stressors. This pilot study suggests that high job strain (specifically, high job demand), as well as low coworker support, are important factors affecting work injury in Japanese female blue-collar workers. Further research with a large number of male blue-collar workers will be required to seek other factors that may be associated with work injury.
To clarify the combined effects of organic solvents and noise on hearing, the upper limit of hearing was measured in 48 male workers exposed to organic solvents and/or noise in a factory producing plastic buttons. Measuring the organic solvent concentrations in working environments and breathing zone air, and the noise level in workplaces were also done. The readings suggested that most exposures to organic solvents and/or noise were within the occupational exposure limits. The prevalence rate of the upper limit of hearing below 75 th percentile curve was higher in workers exposed to organic solvents and noise than expected (25 percent) and the other groups, whereas it was about 25 percent in the noise and control groups. The results suggest that the probable combined effects of organic solvents and noise on hearing should be considered even when the exposures are within the occupational exposure limits.