Immunological abnormalities 17 years after accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Eighteen workers were reviewed 17 years after accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Clinical assessment showed that they were in good health. A study of several biochemical and immunological parameters in these subjects and in 15 carefully matched controls showed no difference in serum concentrations of hepatic enzymes between exposed workers and controls. Although mean serum concentrations of cholesterol and triglyceride were higher in exposed subjects than in controls, the results did not reach statistical significance. Antinuclear antibodies and immune complexes were detected significantly more frequently in the peripheral blood of workers exposed to dioxin. There was no significant difference between exposed workers and controls in the number of T lymphocytes, B lymphocytes, and helper and suppressor T cell counts in peripheral blood, but the number of natural killer cells identified by the monoclonal antibody Leu-7 was significantly higher in workers exposed to dioxin.     

2,3,7,8-四氯二苯并二噁英所致皮肤损害的研究进展

2,3,7,8-四氯二苯并二噁英（2,3,7,8-tetrachlorodibenzop-dioxin,TCDD）是二噁英类化合物中毒性最强的一种,是WHO列出的12类最严重的持续性环境有机污染物之一.TCDD具有亲脂性，体内半衰期长达5，8年，不易排除；对皮肤、免疫系统、生殖系统、消化系统及内分泌系统等都有毒害作用，其中，氯痤疮及与之相关的皮肤及附属器的病变是人类暴露于TCDD后出现的最敏感、最广泛的症状之一。     

A proposed occupational exposure limit for 2,3,7,8-tetrachlorodibenzo-p-dioxin

One contaminant produced unintentionally during the manufacture of chlorophenols and phenoxy herbicides is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The resulting TCDD-containing wastes have been detected at many hazardous waste sites which in recent years have been in the process of remediation. Concerns about worker exposure to TCDD-contaminated soil (dust) during remediation of hazardous waste sites have produced a need for an occupational exposure limit (OEL) for TCDD. The animal toxicology data and human experience with TCDD are reviewed, and an occupational exposure limit for TCDD is proposed. The animal data support risk estimations which are based on TCDD as a nongenotoxic carcinogen. Studies on human populations have failed to demonstrate clearly any significant long-term health effects at levels to which humans have been exposed. The data indicate that an 8-hr time-weighted average limit of 2 ng/m3 is appropriate, and the associated risk would be consistent with other carcinogens at their corresponding OELs. A preliminary OEL of 0.2 ng/m3 (200 pg/m3) is recommended, however, in light of other sources of exposure because of TCDD's ubiquitousness in the environment, its unclear mechanism of action, and its rather long biological half-life in humans. This limit provides an ample margin of safety to prevent chloracne following repeated, acute exposure, and it addresses those chronic effects of TCDD observed in animal studies as well as those observed after accidental human exposure. The resulting body burden caused by chronic exposure to TCDD at the proposed OEL is examined. Its toxicological significance is compared with human tissue data and with other similarly persistent chemicals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral neuropathy after occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Reports of human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) describe signs and symptoms consistent with exposure-related peripheral neuropathy. In a crosssectional study, prevalence of peripheral neuropathy was measured in 265 workers exposed 15 years earlier to chemicals contaminated with TCDD and in 244 unexposed, age-, race-, gender- and community-matched comparisons. Cases of peripheral neuropathy were defined from examination, electrophysiologic and quantitative sensory tests, and symptoms. Exposure was assessed by measuring lipid-adjusted serum TCDD levels. The mean serum TCDD level for workers (220 parts per trillion (ppt)) was significantly higher than for referents (7 ppt) (p < .0001). Thirty-two percent of both worker and referent groups met the case definition for peripheral neuropathy. In the logistic regression analyses, serum TCDD level was not related to peripheral neuropathy. These data suggest that despite continued high serum TCDD levels, peripheral neuropathy is not a long-term sequela of high exposure to TCDD-contaminated chemicals. However, the study cannot preclude the occurrence and subsequent resolution of acute effects caused by high exposure, as experienced in Seveso and possibly by some workers, while exposed to high levels of TCDD-contaminated substances. © 1993 Wiley-Liss, Inc.     

Immunological abnormalities 17 years after accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Eighteen workers were reviewed 17 years after accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Clinical assessment showed that they were in good health. A study of several biochemical and immunological parameters in these subjects and in 15 carefully matched controls showed no difference in serum concentrations of hepatic enzymes between exposed workers and controls. Although mean serum concentrations of cholesterol and triglyceride were higher in exposed subjects than in controls, the results did not reach statistical significance. Antinuclear antibodies and immune complexes were detected significantly more frequently in the peripheral blood of workers exposed to dioxin. There was no significant difference between exposed workers and controls in the number of T lymphocytes, B lymphocytes, and helper and suppressor T cell counts in peripheral blood, but the number of natural killer cells identified by the monoclonal antibody Leu-7 was significantly higher in workers exposed to dioxin.     

A medical follow-up of the health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

The human health effects of long-term exposure to low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have not been well established. The results of a prior study showed that persons exposed to TCDD had depressed cell-mediated immunity, and 18 of 51 persons had anergy or relative anergy on skin testing. This paper presents the results of a medical follow-up on participants who were reported to be anergic or relatively anergic in the earlier study. None of the participants in the follow-up study was anergic, and only one exposed and one unexposed participant were relatively anergic. Several technical and biological possibilities for the difference in results of the two studies are presented. The possibility that recovery from the effects of TCDD exposure caused the differing results is the least plausible explanation for the changes in the skin test results.     

Acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to Mink

The effects of 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD) on adult male mink were assessed. TCDD was administered as a single oral dose (0, 2.5, 5.0, and 7.5 g/kg body weight) and the mink observed for 28 days. There was a dose dependent decrease in feed consumption with corresponding body weight loss. Gross necropsy revealed mottling and discoloration of the liver, spleen, and kidneys. In mink exposed to higher doses of TCDD, brain, kidneys, heart, and thyroid and adrenal glands were enlarged when expressed as a percent of body weight. Hematologic and thyroid hormone measurements in surviving animals revealed no alterations resulting from TCDD exposure. A 28-day LD50 value of 4.2 g/kg body weight was calculated. These results indicate that mink are among the most sensitive species to TCDD and that they can serve as a valuable model to study the impact of environmental dioxins on carnivorous mammalian species.This publication is the result of work supported by the U.S. Department of Agriculture under contract number 59-32U4-4-30 and published with the approval of the Michigan Agricultural Experiment Station as Journal Article No. 12250.     

四氯并二(口恶)(口英)的肝脏毒性

2,3,7,8-四氯二苯并二口恶口英(2,3,7,8-tetra-chlorodibenzo-p-dioxin,TCDD)是一种强烈的持久存在的环境毒素,是世界上毒性最强的化合物之一。它对人体及动物的生物学危害不仅仅涉及皮肤、生殖系统、免疫系统、神经系统等,同时也将对其进行生物转化的肝脏作为它的主要储存部位和重要的靶器官[1,2]。1976年7月9日,位于意大利Seveso的美达镇,发生了TCDD外泄事件,当时有2kg的TCDD泄漏,导致附近的土地严重污染,居民发生各种病变,周围人群的健康状况追踪调查发现,人群中出现肝脏功能异常[3]。从此,TCDD的肝脏毒性便成为研究的热点为科学…     

Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

There is conflicting research regarding an association between fetal death and paternal exposure to Agent Orange, a phenoxy herbicide widely used in Vietnam that was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Men who worked in the U.S. factories that produced Agent Orange were exposed to TCDD at levels hundreds of times higher than TCDD levels in the general population. Wives of TCDD-exposed chemical workers and wives of nonexposed neighborhood referents were interviewed to determine reproductive history. Paternal serum TCDD level at time of conception was estimated for each pregnancy using serum samples taken in 1987. Estimated TCDD levels of workers during or after exposure were high (median, 254 ppt; range, 3-16,340 ppt) compared to referent levels (median, 6 ppt; range, 2-19 ppt). No association between paternal TCDD level at the time of conception and spontaneous abortion was observed among pregnancies fathered by workers with TCDD levels of < 20 ppt [odds ratio (OR) = 0.77; 95% confidence interval (CI), 0.48-1.22], 20 to < 255 ppt (OR = 0.81; 95% CI, 0.40-1.63), 255 to < 1,120, (OR = 0.69; 95% CI, 0.30-1.58), and >or= 1,120 ppt (OR = 0.95; 95% CI, 0.42-2.17) compared to pregnancies fathered by referents. The sex ratio [males/(males + females)] of offspring also did not differ by TCDD exposure (0.53 and 0.54 among workers and referents, respectively). We did not find an association between paternal serum TCDD level and spontaneous abortion or sex ratio of offspring in this population. The estimated TCDD levels in this exposed worker population were much higher than in other studies, providing additional evidence that paternal TCDD exposure does not increase the risk of spontaneous abortion at levels above those observed in the general population. The study could not evaluate the effect of father's childhood or prenatal TCDD exposure on subsequent sex ratio.     

四氯并二噁英的肝脏毒性

2，3，7，8—四氯二苯并二噁英(2，3，7，8—tetrachlorodibenzop-dioxin，TCDD)是一种强烈的持久存在的环境毒素，是世界上毒性最强的化合物之一。它对人体及动物的生物学危害不仅仅涉及皮肤、生殖系统、免疫系统、神经系统等，同时也将对其进行生物转化的肝脏作为它的主要储存部位和重要的靶器官。1976年7月9日，位于意大利Seveso的美达镇，发生了TCDD外泄事件，当时有2kg的TCDD泄漏，     

亚慢性染毒2,3,7,8-四氯二苯并二(口恶)英对雄性大鼠生殖系统的影响

目的 了解2,3,7,8-四氯二苯并二(口恶)英(TCDD)对雄性大鼠生殖系统的影响.方法 清洁级Wistar雄性大鼠32只,体重(100±10)g,随机分成4组,每组8只,连续经口灌胃染毒90d,剂量分别为2.5,25,250 ng/kg,对照组给予二甲基亚砜(DMSO),测定血清中睾酮(T)、促黄体生成素(LH)、促卵泡生成素(FSH)的激素水平以及睾丸、前列腺、精囊腺的脏器质量系数,附睾尾精子畸形率.结果 与对照组比较,各染毒组T水平下降,差异有显著性(P＜0.05);各染毒组FSH和LH水平上升,但差异无显著性(P＞0.05);中、高剂量组的睾丸、精囊腺及所有染毒组的前列腺脏器质量系数均低于对照组(P＜0.05);各染毒组精子畸形率随剂量的增加而上升,中、高剂量组与对照组相比差异显著(P＜0.01).结论 TCDD亚慢性染毒,可影响精子和生殖系统的正常发育,并在一定程度上对生殖激素的稳态造成了干扰.     

Persistence of decreased T-helper cell function in industrial workers 20 years after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

In experimentally exposed animals 2,3,7,8-tetrachlorodibenzo-n-dioxin (TCDD) causes severe immunosuppression. However, the overall susceptibility of humans for the different pathological effects of TCDD has remained unclear. We examined the long-term effects of TCDD in 11 industrial workers who were exposed to high doses of TCDD for several years 20 years ago. Current TCDD body burdens were still at least 10 times higher (between 43 and 874 pg/g blood far) in these exposed persons than in the average German population. To evaluate possible TCDD-induced changes in the percentage of different lymphocyte subsets, we determined a large panel of lymphocyte subsets in the blood by flow cytometric analysis. Immunocompetence of T-and B-lymphocytes was tested by nitrogen (phytohemagglutinin, pokeweed mitogen)- induced lymphoproliferation assays and by assays using sensitive mixed-lymphocyte cultures. No significant differences could be detected between the individuals tested and controls for surface marker distribution or mitogen-induced lymphoproliferation TCDD-exposed subjects showed a reduced response to human lymphocyte antigen-allogeneic lymphocytes and interleukin-2-boosted proliferation. Responder cells of the dioxin-exposed persons proliferated less in response to irradiated stimulator cells (p < or = 0.05), and the third-party mixed lymphocyte reaction against unirradiated stimulator cells revealed suppressive activity in the responder cell fraction compared to the controls (p < or = 0.01). Furthermore, the capacity of a pool of T cells isolated from TCDD-exposed subjects to proliferate upon interleukin-2 stimulation was significantly diminished (p < or = 0.05). TCDD has a long-term immunosuppressive-effect on T-helper cell function, which is mediated more likely by a reduced functionality of individual cells rather than by a reduction in absolute cell numbers in the peripheral blood.     

Cancer risk for chemical workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Aims: To describe the long term mortality experience of a cohort of 2187 male chemical production workers previously exposed to substantial levels of dioxin.

Methods: Vital status for a previously identified cohort was determined for an additional 10 years, to 1995. Dioxin exposures took place before 1983 and were sufficient to result in chloracne in 245 individuals. Mortality rates were compared with national figures and with a large pool of co-workers in unrelated production jobs.

Results: All cancers combined (standardised mortality ratio (SMR) = 1.0, 95% CI 0.8 to 1.1) and lung cancer (SMR = 0.8, 95% CI 0.6 to 1.1) were at or below expected levels. Rates for soft tissue sarcoma (SMR = 2.4, 95% CI 0.3 to 8.6) and non-Hodgkin's lymphoma (SMR = 1.4, 95% CI 0.6 to 2.7) were greater than expected overall, but below expectation in the update period. No trend of increasing risk with increasing exposure was observed for these cancers. Workers who developed chloracne had very low all-cancer rates (SMR = 0.5, 95% CI 0.3 to 1.0), and lung cancer rates (SMR = 0.3, 95% CI 0.0 to 1.1).

Conclusions: We found no coherent evidence of increased cancer risk from dioxin exposure in this cohort. Our study highlights the wide range of cancer rates and the lack of consistency across dioxin studies.

     

Biochemical, neuropsychological, and neurological abnormalities following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure

Presented herein are the results of follow-up examinations of 13 workers performed in 1996--30 yr following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication in a herbicide production plant. In these workers, the current mean plasma level of 2,3,7,8-TCDD, measured by high-resolution gas chromatography/high-resolution mass spectrometry, was 256 pg/gm lipid (range = 14-760 pg/gm lipid). This mean value corresponded to an estimated concentration of approximately 5,000 pg/gm plasma fat that existed about 30 years ago. Such a mean plasma level indicates that this group was one of the most heavily exposed groups to 2,3,7,8-TCDD described in the literature. Patients with persistent chloracne had significantly higher plasma levels of 2,3,7,8-TCDD than persons without chloracne. A significant, positive correlation was found between plasma levels of 2,3,7,8-TCDD in 1996 and levels of cholesterol and plasma lipids that existed since 1974. During 1996, there was a significant positive correlation between 2,3,7,8-TCDD and levels of beta-lipoproteins, cholesterol, and triglycerides. Also in 1996, significant correlations were found between neuropsychological variables and plasma levels of 2,3,7,8-TCDD. Other significant correlations were observed between neuropsychological variables and (1) the highest levels of triglycerides (i.e., since the year 1989), (2) levels of triglycerides in 1996, (3) levels of cholesterol at the first examination (i.e., 1969-1970), (4) highest level of cholesterol since the year 1969, and (5) cholesterol levels in 1996. Such correlations are biologically plausible, and they provide evidence of impaired cognitive performance (i.e., memory first), with a concurrent increase of plasma lipid levels. Abnormal electromyography, electroencephalography, and visual evoked potentials were observed in 23%, 54%, and 31 %, respectively, of former workers. Abnormal electroencephalography findings occurred more frequently in workers who had 2,3,7,8-TCDD blood levels that exceeded 200 pg/gm plasma fat than in workers with 2,3,7,8-TCDD values lower than 200 pg/gm plasma fat (p < .025). Frequency of polyneuropathic EMG abnormalities decreased from 38% in the 1970s to 23% in 1996. Improvement of conduction velocity in the tibial nerve was statistically significant (p < .05).     

Levels of polychlorinated dibenzo-p-dioxins and dibenzofurans in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Review of employment and chemical production records at a Missouri chemical plant and of questionnaires with self-reported occupational exposure to 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2,3,7,8-TCDD) for 16 Missouri workers has explained the wide diversity of 2,3,7,8-TCDD levels previously reported in the workers' adipose tissue (3.5-750 ppt on whole-weight basis). We show that the highest exposures reported to date in the United States occurred in a group of nine production workers who made products contaminated with 2,3,7,8-TCDD. The nine workers had adipose tissue levels with a mean of 246 ppt and a range of 42 to 750 ppt. Seven persons who worked at the same chemical company, but not in the 2,3,7,8-TCDD-contaminated process, had a mean of 8.7 ppt and a range of 3.5 to 25.8 ppt. We also report serum levels of 2,3,7,8-TCDD in these individuals. The adipose tissue from a subset of four production workers with elevated levels of 2,3,7,8-TCDD and seven Missouri residents with normal 2,3,7,8-TCDD levels was also analyzed for other isomers of the PCDDs and PCDFs. The mean adipose tissue level of 2,3,7,8-TCDD in the subset of production workers was 45 times higher than the mean level in the unexposed Missouri residents, but similar levels of the other PCDDs and PCDFs were found in both groups.     

Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne

Chloracne was found in 52% of 226 workers in a 1979 cross-sectional survey at a plant where 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) had been manufactured from 1948 to 1969. Mean duration of residual chloracne was 26 years, and in 29 subjects, it had been present for 30 years. A significant increased prevalence of abnormal gamma-glutamyl transpeptidase (GGT) and higher mean GGT were found in those with chloracne, compared to those without. Although mean triglyceride values were higher in those with chloracne, the difference was not statistically significant. Neurological examination showed a statistically significant higher prevalence of abnormal sensory findings in those with chloracne. Increased prevalence of angina and reported myocardial infarction in those with chloracne was not significant when age-adjusted. Increased prevalence of reported sexual dysfunction and decreased libido in those with chloracne compared to those without was statistically significant after age adjustment. No differences were found between those with and without chloracne in serum cholesterol, total urinary porphyrins, or in reproductive outcome.     

Effects of dietary exposure of mink (Mustela vison) to 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 2,3,7,8-tetrachlorodibenzofuran on reproduction and offspring viability and growth

This study assessed the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) on the reproductive performance of female mink (Mustela vison) and the viability and growth of their offspring. Nine adult female mink were randomly assigned to one of 13 dietary treatments (one control and four doses each of TCDD, PeCDF, and TCDF [2.1-8.4, 4.0-15 and 5.2-25 ng TCDD toxic equivalents (TEQ)/kg body wt/d]). Diets were fed from two months prior to breeding through weaning of offspring at six weeks of age. At least nine kits per treatment group were maintained on their diets through 27 weeks of age. There were no effects on litter size or viability of offspring. No consistent effects were observed on body mass or relative organ masses of animals at any age. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and PeCDF accumulated in the liver and adipose tissue, but TCDF cleared rapidly. The lack of significant effects on reproduction and offspring viability contrasts with effects reported for mink exposed to environmentally derived PCB mixtures with equivalent TCDD potencies. This suggests that it may be inappropriate to apply toxicity reference values associated with PCB mixtures to animals also exposed to TCDD, PeCDF, or TCDF, and the World Health Organization TCDD toxic equivalency factors for some congeners may not be appropriate for mink.