The early effects of 2, 3, 7, 8-tetrachlorodibenzo-para-dioxin (TCDD) exposure in the population involved in the Seveso, Italy, incident in 1976, have been examined in numerous studies. Chloracne was the only effect linked with sufficient certainty to dioxin exposure. The possible longterm consequences were investigated with mortality and cancer incidence studies. Mortality and morbidity findings during the 20-year period following the accident showed increased risk from lymphoemopoietic neoplasm, digestive system cancer (rectum in males, and biliary tract among females, in particular) and respiratory system cancer (lung, among males). In the incidence analyses, also thyroid gland and pleura cancer appeared suggestively increased. Soft tissue sarcomas showed an increase in the largest, yet least exposed, exposure sub-cohort. Several hypotheses associating non-cancer effects with dioxin exposure were corroborated by findings in the Seveso population: this was the case with cardiovascular effects (possibly linked to both chemical exposure and stressful disaster experience), endocrine effects (diabetes among females) and reproductive effects: exposure of men to TCDD was linked to a lowered male/female sex ratio in their offspring. The results of many Seveso studies point to possible gender effects, in accordance with animal models. Notwithstanding the acknowledged study limitations (lack of individual exposure markers, short latency, and small population size for certain cancer types), results of previous experimental and epidemiological studies, along with mechanistic knowledge on dioxin toxicity, support the hypotheses that the observed excesses might be associated with dioxin exposure. The mortality and cancer incidence follow-up of the Seveso cohort are continuing.

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The aim of the present paper is to summarize the history of the Yusho incidence that occurred in the western part of Japan in 1968. A strange disease was reported in October 1968. This strange disease was characterized by acne-like eruptions, pigmentation of the skin, and eye discharge, and it was named Yusho (oil disease). Through systematic epidemiological studies based on observation of initial case series, and extensive efforts to clarify causal agents by the Study Group for Yusho, it was concluded that Yusho was caused by ingestion of rice oil contaminated with PCBs and PCDFs. As of now, more than 1, 800 patients, have been registered as having Yusho and around 300 are deceased. Clinical observation showed that typical symptoms of Yusho have decreased, even general fatigue, headache and numbness of extremities have still been complained by patients. No effective treatment has been found so far. Careful and systematic observation for Yusho patients and medical care services should be continued for a further understanding of Yusho.

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In order to determine whether Agent Orange exposure was associated with increased frequency of medical problems, we conducted a cross-sectional epidemiologic study of Korean veterans during 1995-1996. 1, 224 Vietnam and 154 non-Vietnam veterans were included in the study. Exposure to Agent Orange was assessed by structured in-depth interview on the participants' history of service in Vietnam. Health outcomes were assessed by a standardized comprehensive clinical investigation by a group of clinical specialists. The differences in the prevalence of various medical diagnoses were assessed by Cochran-Mantel-Haenszel chi-square tests comparing the exposure levels of Vietnam veterans, adjusting for age. Multiple logistic regression was performed to estimate the effect of “service in Vietnam” adjusting for age, smoking, alcohol, body mass index, education, and marital status. Vietnam veterans had an increased frequency of eczema (odds ratio [OR]=6.54), radiculopathy (OR=3.98), diabetes (OR=2.69), peripheral neuropathy (OR=2.39), and hypertension (OR=2.29), compared to non-Vietnam veterans, adjusting for potential confounders. In addition, higher levels of exposure among Vietnam veterans were associated with increased frequency of ischemic heart disease (p<0.01), valvular heart disease (p<0.01), and retinopathy (p<0.01). We conclude that exposure to Agent Orange is associated with various health impacts in Korean Vietnam veterans.

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Immunomodulatory effects of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) demonstrated using animals are thymic atrophy, downregulation of cytotoxic T or B lymphocyte differentiation or activation, whereas human immunotoxicities have not been investigated well. This study was undertaken to evaluate overall immunologic spectrum of the Vietnam War Korean veterans exposed to Agent Orange contaminated with TCDD. Quantity of red blood cells, hemoglobin and hematocrit in the veterans suffered from chronic diseases associated with Agent Orange exposure (Veteranspatient group) were decreased in comparison with those of the veterans without the diseases and the age-matched healthy controls, but no differences in leukocyte populations. Plasma IgG levels were lowered in the veterans than the controls, owing to significant decrease in the IgG1 levels. Increase in the IgE levels was observed in the plasma from the veterans. Alteration of T cell-mediated immunity was also resulted from activation of peripheral blood mononuclear cells with polyclonal T cell activators. Production of IFNγ, a major cytokine mediating host resistance against infection or tumoregenesis, was lowered in the veterans-patient group. However, production of IL-4 and IL-10, representative cytokines involved with hypersensitivity induction, was enhanced in the patient group. Overall, this study suggests that military service in Vietnam and/or Agent Orange exposure disturbs immune-homeostasis resulting in dysregulation of B and T cell activities.

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In Japan, the largest source of dioxin is solid waste incineration plants. Because workers employed at these plants handle fly ash and slag contaminated by dioxins, they can take dioxins into the body during work and their health may be adversely effected. This paper describes the dioxin exposure concentration, daily dioxin intake and blood dioxin level in workers employed at municipal incineration plants. The estimated dioxin exposure concentrations were 0.5 to 7.2 pg TEQ/m³ in the daily operation and 0.2 to 92, 000 pg TEQ/m³ in the periodic maintenance. It was also expected that the daily dioxin intake can exceed the tolerable daily intake (TDI) in incineration plants with fly ash of high dioxin concentration. The mean of blood dioxin concentration was 346 pg TEQ/g lipid in the highest exposed worker group of the Toyono-gun incineration plant and those were 11 to 40 pg TEQ/g lipid in the other incineration plants.

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Low-levels of dioxin cause cancer in animals. In 1997 dioxin was found to be a human carcinogen by the International Agency for Research on Cancer, based largely on four studies of industrial workers exposed to high levels. Recently there has been interest in estimating human cancer risk at low level environmental exposures. Here we review quantitative exposure-response analyses and risk assessment for low environmental levels based on the largest existing cohort of workers exposed to dioxin (the U.S. NIOSH cohort). We estimate that doubling background levels of exposure, which may occur for example by eating a lot of fish which have accumulated dioxin, will increase lifetime risk of cancer death by 0.1 to 1.0%. In the US the background risk of cancer death by age 75 is 12%, so doubling background levels of dioxin exposure would increase this lifetime risk to somewhere between 12.1 and 13.0%. Our results agree broadly with results from a German cohort, which is the only other cohort for which a quantitative risk assessment has been conducted.

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Hazardous substances, such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) also have been detected in Municipal Solid Waste (MSW) and industrial waste incinerators in Korea. In this study, we estimated the exposure status of these hazardous substances and their heath effects in workers and residents near the MSW incinerators and residents near the industrial waste incinerators. We interviewed 13 workers and 16 residents from the area around the two MSW incinerators, and further 10 residents from the area around one industrial waste incinerator, which is suspected to emit higher hazardous substances. During the interview we collected information including sociodemographic information, personal habits, work history, detailed gynecologic and other medical history. Blood samples from 45 subjects were also collected for analysis of PCDDs and PCDFs, which were analyzed by HRGC-HRMS (High Resolution Gas Chromatography - High Resolution Mass Spectrometer). In addition to a questionnaire survey, urinary concentrations of 8-hydroxydeoxyguanosine (8-OH-dG) and malondialdehyde (MDA) were measured as oxidative injury biomarkers. Urinary concentrations of 8-OH-dG were determined by in vitro ELISA (JAICA, Fukuroi, Japan). MDA were determined by HPLC using adduct with TBA (thiobarbituric acid). The PCDD/F concentrations in residents from the area around industrial waste incinerator were higher than those in workers and residents from the area around MSW incinerator. The average toxic equivalency (TEQ) concentrations of PCDD/Fs in residents from the area around industrial waste incinerator were 53.4 pg I-TEQs/g lipid. The average TEQ concentrations of PCDD/Fs in workers and residents near MSW incinerator were 12.2 pg I-TEQs/g lipid. Estimated daily intake (EDI) of each person was calculated, and the EDI of all workers and residents near MSW incinerator were within the tolerable daily intake range. But for only 30% of 10 people near the industrial waste incinerator were the EDI within the tolerable daily intake range (1-4 pg I-TEQ/kg bw/day) suggested by WHO (1997). The oxidative stress of residents near the industrial waste incinerator was higher than that in workers and residents from the area around MSW incinerator. This oxidative stress may have been caused by hazardous substances, such as PCDD/Fs emitted by incinerators. The residents from the area around industrial waste incinerator were exposed to hazardous substances such as PCDD/ Fs. Proper protection strategies against these hazardous chemicals are needed.

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In September 1998 the Ministry of Health and Welfare announced that high concentrations of dioxins were detected in the samples of soil near the incinerator and ash, drainage, sludge and others remained in the furnace and air pollution control devices of municipal solid waste incinerator (MSWI) in rural part of Osaka Prefecture. According to the results the Ministry of Labor immediately organized the “Research and investigation committee on the dioxin problem of Toyono-gun Clean Center” under Japan Industrial Safety and Health Association to investigate the health effects of chronic exposure to dioxins and its accumulation on workers of the incinerator plant. The investigation was carried out in Sept 1998 and from the results, the committee concluded that the concentrations of dioxin among the blood of the workers who had engaged in maintenance of the furnace, the electric dust collector, and the wet scrubber of the incinerator were higher compared with those of residents in surrounding areas. However, there were no signs or findings correlating to blood level of dioxns, and the level was not high enough to induce sufficient health effects from the review of published papers. According to the results of this survey the committee understood that the follow-up study of blood dioxins level of group III and IV workers was inevitable and concerned about the other MSWI workers in Japan who might also be exposed to similar level of dioxins. The Ministry of Labor decided to expand the survey to other MSWI workers in Japan as 3-year project from 1999. The summarized report on the project is appended in this paper.

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We have improved the method of measuring dioxins in the blood of Yusho patients; with this improved method, it is possible to take measurements quickly and precisely, using as little as 5g of blood. The specific points of improvement of this method are the extraction of lipids from blood by accelerated solvent extractor (ASE), the miniaturization of column cleanup for the purification of dioxins, and the use of a solvent cut large volume (SCLV) injection system with high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Using this improved method of analysis, we are currently investigating dioxins in the blood of 400 Yusho patients collected in Japan in 2002. We here describe the details of our announcement at Dioxin 2002 Symposium about the improvement of this analysis method, and discuss several other modifications

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Many of the biological and toxic responses of polychlorinated dioxins and furans (PCDD/Fs) have been shown to be mediated through the aryl hydrocarbon receptor (AhR). Several bioanalytical methods have been developed to analyze Ah receptor agonists in cost-and-time effective way such as CALUX-bioassay (chemical-activated luciferase gene expression). This bioassay can detect the sum of dioxin-like activity (including unknown substances) in complex waste and environmental samples. The present paper gives a description of the bioanalytical method and application examples to analyze dioxin-like compounds in waste management samples of thermal/chemical dechlorination processes. The current detection limit of the CALUX in rat hepatoma H4IIE recombinant cells is less than 1 pM TEQ (0.06 pg TEQ/well). The CALUX bioassay is considered to be useful tools for the rapid and integrated monitoring of environmental emission and residual samples as a pre-screening or in combination to chemical analysis.

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This manuscript reviewed the neurotoxicity of dioxins and related compounds with an emphasis on maternal exposure. The brain during developmental period is thought to be highly sensitive to dioxin and its related compounds that affect a broad range of brain functions from the advanced brain function to the reproduction-controlling function, even at low doses. It is suggested that dioxins exhibit endocrine-disrupting action on the gonadal and thyroid hormone axes, as well as the 'neural-disrupting action' on neural transmission and neural network formation. From behavioral toxicological studies as well as studies on the underlying mechanisms of dioxins' toxicity, dioxins affect some specific functions in particular regions or cells of the brain at critical windows during the developmental period.

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The objective of the present study was to examine if the mortality due to tuberculosis and cancer in the lungs was elevated in a cohort of 200 male whetstone cutters. 1955-1995 death certificatebased mortality data on the cohort were available, and the data were reviewed in the present study for mortality due to the two diseases to calculate standardized mortality ratios (SMR) in reference to the health statistics of Kyoto prefecture, where the cohort lived. Among the 200 cohort members, 99 men deceased during the observation period, the deaths including 10 cases of lung tuberculosis (of which 9 cases had silicosis together), 20 cases of all malignancies, and 6 cases of lung cancer (5 cases with silicosis). There was a significant elevation in the mortality due to lung tuberculosis (SMR=3.47) although SMR for all causes was not elevated (1.10). There was no significant change in SMR for all malignancies (0.78), whereas SMR for lung cancer (1.24) tended to be elevated although insignificantly. Lung tuberculosis was a significant complication of silicosis in 1955-1995. Possible elevation in lung cancer SMR among this cohort needs further studies.

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We conducted a 1-year follow-up study to evaluate the lasting effect of psychosocial characteristics on quality of life among Japanese civil servants. For this purpose, sense of coherence (SOC), which has been associated with adoptive measures in responding to life stress, and job strain components of demand and control, were used. We evaluated 1392 civil servants working in departments related to the municipality of T city in Toyama prefecture, Japan, in the springs of 2001 and 2002 with complete information in both phases of the study. Using validated Japanese versions of WHOQOL-BREF (WHO/QOL-26) and SOC-13 and a self-reported questionnaire on job demand and control in the workplace, we conducted multiple linear regression analysis to assess the effects of above-mentioned characteristics on WHO/QOL-26 domains. After entering first phase scores, age, sex, employment category and negative affectivity into the models, SOC was associated positively with second phase scores in all domains of WHO/QOL-26 (standardized β coefficients of 0.21, P<0.01; 0.12, P<0.001; 0.13, P< 0.001 and 0.07, P<0.05 for Physical Health, Psychological, Social Relationship and Environment, respectively). In addition job control was related positively to Physical Health, Psychological and Social Relationship domains (standardized β coefficient of 0.10, p<0.001; 0.12, p<0.05 and 0.07, p<0.05, respectively), while job demand was negatively related to Physical Health domain with a β coefficient of -0.11, p<0.001. Higher sense of coherence and job control could result in better subjective feeling of well-being in a 1-year follow-up among Japanese civil servants.

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3, 3'-dichlorobenzidine (DCB) is suspected to be carcinogenic in experimental animal and human. Several studies have investigated excretion of metabolites in urine, hemoglobin adduction and cancer incidence among workers exposed occupationally to DCB. In these researches, metabolites of DCB had a very important role. The purpose of this study was to develop the urinary monitoring method of its metabolites from rats exposed with DCB, by easily synthesizing them in the laboratory. N, N'-diacetyl-DCB was easily synthesized with DCB in pyridine by adding sufficient acetyl chloride or acetic anhydride. N-acetyl-DCB was isolated from the supernatant, which made by adding 21μl acetyl chloride (more 3 times than DCB in moles) to 32 mg DCB in 2 ml pyridine and 0.3 ml acetic acid. Gas chromatography/mass spectrometry (GC/MS) was used for the identification, gas chromatography nitrogen phosphorous detection (GC-NPD) for the quantification and gas chromatography flame ionization detection (GC-FID) for the determination of purity. The base peak of DCB, N-acetyl-DCB and N, N'-diacetyl-DCB was 252 m/z. The other main peaks were 294 m/z for N-acetyl-DCB, and 294 and 336 m/z for N, N'-diacetyl-DCB. The purities of N-acetyl-DCB and N, N'-diacetyl-DCB were identified as 98.82 and 98.72% by GC-FID, respectively. After treatment orally to rats with 20mg DCB/kg body weight for 2 weeks, the urinary excretion amount of DCB was nearly constant at range of 0.11-0.18 mg/L for 2 weeks. But excretion of N-acetyl-DCB was continually increased from 1.30 mg/L on 1st day to 4.15 mg/L on 14th day. And level of N, N'-diacetyl-DCB in urine was sharply increased from 2.13 mg/L on 1st day to 11.00 mg/L on 14th day.

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The X-ray diffraction method and the phosphoric acid method are widely used to determine the fraction of free silica (mainly quartz and other silica polymorphs) in respirable dust sampled in working environments in Japan. In this study, we clarified the size effect of quartz dust for the Xray diffraction method and the phosphoric acid method using size controlled quartz samples. The quartz samples were classified into 6 fractions with different size ranges: 1 μm and smaller, 1 to 3 μm, 3 to 5 μm, 5 to 7 μm, 7 to 10 μm and 10 μm and larger. Both of the determination methods were affected by the particle size, and especially particles smaller than 3 μm fairly dissolved in hot phosphoric acid and reduced X-ray diffraction intensity remarkably. If the content of these fine particles in the standard quartz sample is lower than that of the test samples, the fraction of free silica may be underestimated by these methods. For this reason, the standard quartz sample should have a representative size distribution of the field samples. The dust samples containing quartz were collected at a foundry and dissolved by phosphoric acid to remove non-quartz materials. The size fractions of dissolved samples were 50% for 5-10 μm, 25% for 3-5 μm, 20% for 1-3 μm and 5% for 1 μm and smaller. As the size distribution is similar to the present standard sample widely used in Japan, we concluded that the standard sample is suitable for these determination methods.

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Occupational health of traffic policemen employed at six major towns of north India was monitored during these investigations. Traffic controllers face the risk of exposure to benzene present in the ambient air as a component of fuel exhaust. Inhaled benzene is metabolized and excreted as phenol. Our observations on urinary phenol show much higher values than prescribed by ACGIH. Furthermore, social habits like alcohol consumption and cigarette smoke were found to modulate benzene metabolism. It was noticed that cigarette smoke synergizes the effect of benzene whereas antagonistic effects of alcohol were observed.

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Although byssinosis in jute mill workers remains controversial, studies in a few jute mills in West-Bengal, India, revealed typical byssinotic syndrome associated with acute changes in FEV₁ on the first working day after rest. The present study on 148 jute mill workers is reported to confirm the occurrence of byssinosis in jute mill workers. Work related respiratory symptoms; acute and chronic pulmonary function changes among exposed workers were studied on the basis of standard questionnaire and spirometric method along with dust level, particle mass size distributions and gram- negative bacterial endotoxins. The pulmonary function test (PFT) changes were defined as per the recommendation of World Health Organization and of Bouhys et al. Total dust in jute mill air were monitored by high volume sampling, technique (Staplex, USA), Andersen cascade impactor was used for particle size distribution and personal exposure level was determined by personal sampler (Casella, London). Endotoxin in airborne jute dust was analysed by Lymulus Amebocyte Lysate (LAL) “Gel Clot” technique. Batching is the dustiest process in the mill. Size distribution showed that about 70-80% dust in diameter of <10 μm, 40-50%, <5 μm and 10-20%, <2 μm. Mean endotoxin levels found in batching, spinning and weaving, and beaming were 2.319 μg/m³, 0.956 μg/m³, 0.041 μg/m³ respectively and are comparable to the values obtained up to date in Indian cotton mills. Respiratory morbidity study reported typical byssinotic symptoms along with acute post shift FEV₁ changes (31.8%) and chronic changes in FEV₁ (43.2%) among exposed workers. The group with higher exposure showed significantly lower FVC, FEV₁, PEFR and FEF_25-75% values. The study confirmed the findings of the earlier studies and clearly indicated that the Indian jute mill workers are also suffering from byssinosis as observed in cotton, flask and hemp workers.

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To assess the exposure of welders to thorium-232 (²³²Th) during tungsten inert gas arc (TIG) welding, airborne concentrations of ²³²Th in the breathing zone of the welder and background levels were measured. The radioactive concentrations were 1.11 × 10^-2 Bq/m³ during TIG welding of aluminum (TIG/Al), 1.78 × 10^-4 Bq/m³ during TIG welding of stainless steel (TIG/SS), and 1.93 × 10^{- 1} Bq/m³ during electrode sharpening, with 5.82 × 10^-5 Bq/m³ background concentration. Although the annual intake of ²³²Th estimated using these values did not exceed the annual limit intake (ALI, 1.6 × 10² Bq), we recommend reducing ²³²Th exposure by substituting thoriated electrodes with a thorium-free electrodes, setting up local ventilation systems, and by using respiratory protective equipment. It is also necessary to inform workers that thoriated tungsten electrodes contain radioactive material.

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To disclose the effects of chromium (Cr) on olfactory function, olfactory threshold tests were conducted on 27 male plating workers (Cr workers) with signs and symptoms of olfactory irritation but without nasal septum perforation or ulcer and on 34 male control subjects in Korean plating factories. The Cr workers had been exposed to Cr fume for 0.9 to 18.2 (mean 7.9) years; their blood Cr concentrations (0.16-3.69, mean 1.29 μg/dl) were significantly higher than those of the 34 control subjects (0.04-1.95, mean 0.55 μg/dl). Scores on recognition thresholds among the Cr workers were significantly higher than those of the control subjects (p<0.05) and related positively and significantly to the exposure periods of the 27 Cr workers (p<0.05). Olfactory thresholds were not significantly different between the Cr workers with and without nasal signs or symptoms, except that the scores on the recognition threshold were significantly higher in those experiencing difficulty with smell (p<0.05). It is suggested that olfactory threshold is affected by Cr without development of nasal septum perforation or ulceration.

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We investigated a simple method using induced ovulation in immature rats to detect ovarian injury due to chemicals. We investigated the influence of di-(2-ethylhexyl) phthalate (DEHP) on ovulation induced by equine chorionic gonadotropin (eCG) in immature F344 rats. Single injections of 15 and 30 iu eCG induced ovulation in 4 of 6 rats and in all of 4 rats, respectively. The mean number of ovulated ova was 12.7 in the 15 iu eCG group and 8.0 in the 30 iu group. When rats received 4 daily doses of DEHP at 500 mg/kg, ovulation occurred in 4 of 6 rats in the 15 iu eCG group and in 1 of 3 rats in the 30 iu group. Mean numbers of ovulated ova were 2.50 and 0.33 ova in the 15 and 30 iu groups, respectively. Changes in ovarian and uterine weights were not found. Inhibition of ovulation by the injection of DEHP indicated the utility of induced ovulation in immature rats to detect reproductive toxicity in females.

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Single intraperitoneal injection of lead acetate (200 mg/kg b.w) to Swiss mice stimulated testicular weight loss with a constant increase in the incidence of abnormal sperm population and decrease in the total sperm count. Testicular ascorbic acid also declined significantly during the post-treatment phase with significant rise in Lipid Peroxidation Potential (LPP) of the tissue. Elevated LPP is indicative of oxidative stress in treated mice testes. The possible role of lead-induced oxidative stress in culminating increased sperm abnormality and decreased sperm count have been discussed. Further, possible antioxidative role of testicular ascorbic acid in minimizing oxidative stress in leadtreated mice has been demonstrated.

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Formaldehyde (HCHO) exposure in industry causes health impairment, especially immune profile. Male albino rats when exposed to HCHO at 5, 10, 15 mg/kg day for 30 days showed decrease in thyroid weight in 10, 15 mg/kg/day HCHO fed group with commensurate follicular regression (epithelial cells), decreased triiodothyronine (T₃), thyroxin (T₄) deficiency and enhanced thyroid stimulating hormone (TSH). Repeated chemical stimulation might have increased thyroid activity of the follicles and rapidly deteriorated the capacity for synthesis of thyroxin hormone and thus becomes atrophied. The chronic action of HCHO on thyroid may be due to a block at the source of thyroid hormone (s).

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