Adverse health effects in humans exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

The environmental contaminant 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) belongs to the category of highly toxic, persistent organic pollutants that accumulate in animal fat and plant tissues. Today, background TCDD levels in human fat are showing a decreasing trend. The food chain is the main source of exposure in the human population. TCDD regulates the expression of a wide range of drug-metabolizing enzymes and has an impact on a large number of biological systems. The most pronounced effects have occurred in occupational settings following the uncontrolled formation of TCDD after industrial accidents, as well as in rare intentional intoxications. Although the acute effects of TCDD exposure are well described in the literature, the long-term consequences have been underevaluated. The most well-known symptoms of severe acute intoxication are chloracne, porphyria, transient hepatotoxicity, and peripheral and central neurotoxicity. Because of the long-term persistence of TCDD in the human body, atherosclerosis, hypertension, diabetes, vascular ocular changes, and signs of neural system damage, including neuropsychological impairment, can be present several decades after massive exposure. Such chronic effects are nonspecific, multifactorial, and may be causally linked to TCDD only in heavily intoxicated subjects. This opinion is supported by the dose-dependent effect of TCDD found in exposed workers and by experimental animal studies.     

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.     

Risk assessment for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on an epidemiologic study

The International Agency for Research on Cancer (Lyon, France) recently concluded that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a human carcinogen. There have been few human studies and risk assessments with quantitative exposure data. The authors previously conducted exposure-response analyses based on estimated external TCDD exposure for 3,538 US male chemical workers and found a positive trend for all cancer with increasing cumulative exposure. In the present study, 1988 data from 170 workers with both estimated external exposure and known serum TCDD levels were used to derive the relation between the two. This derived relation was used to estimate serum TCDD levels over time for all 3,538 workers, and new dose-response analyses were conducted by using cumulative serum level. A positive trend (p = 0.003) was found between estimated log cumulative TCDD serum level and cancer mortality. For males, the excess lifetime (75 years) risk of dying of cancer given a TCDD intake of 1.0 pg/kg of body weight per day, twice the background intake, was an estimated 0.05-0.9% above a background lifetime risk of cancer death of 12.4%. Data from this cohort are consistent with another epidemiologic risk assessment from Germany and support recent conclusions by the US Environmental Protection Agency.     

Fate of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a model aquatic environment

The fate of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) was studied by using aquatic sediment and lake water under laboratory conditions. Most of the TCDD was found in the sediment from which it slowly disappeared. Evaporation may be a major mode of disappearance of TCDD in samples incubated 39 days or more, with metabolism playing only a minor role. Under the experimental conditions the half-life of TCDD was in the order of 600 days. The metabolic activities were enhanced under conditions which stimulated microbial growth in the presence of sediment, and the metabolites were found to be released from the sediment to the ambient water.     

Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects

A variety of health effects have been attributed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but little information is available on the course of a verified high-level TCDD intoxication. In this paper we describe two cases of heavy intoxication with TCDD and present a 2-year follow-up including clinical, biochemical, hematologic, endocrine, and immunologic parameters monitored in two women, 30 and 27 years of age, who suffered from chloracne due to TCDD intoxication of unknown origin. Patient 1, who had the highest TCDD level ever recorded in an individual (144,000 pg/g blood fat), developed severe generalized chloracne, whereas in the second patient, despite heavy intoxication (26,000 pg/g blood fat), only mild facial acne lesions occurred. Both patients initially experienced nonspecific gastrointestinal symptoms. In Patient 1 we observed a moderate elevation of blood lipids, leukocytosis, anemia, and secondary amenorrhoea. The laboratory parameters in Patient 2 were all normal. Despite the high TCDD levels, apart from chloracne, only few clinical and biochemical health effects were observed within the first 2 years after TCDD intoxication.     

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) persistence in the Seveso (Milan, Italy) soil

Preliminary results of a new study on TCDD environmental persistence at Seveso (Milan, Italy) are presented. For this study, the most contaminated territory, Zone A, was divided into areas to fractionate the available TCDD levels in soil into data sets with reduced value spreads. In addition, various time subsets were defined for each area. Selected data were fitted with the exponential model y = y0.e-k.1. It was estimated that at least 1.2 kg TCDD was present in Zone A shortly after the accident. On average, a considerable portion (23%) of this amount lay on vegetation; TCDD which was not photodegraded or volatilized before the heavy rains of fall 1976, was later washed off and transferred to ground by water action. From this study, mean analytical underestimations affecting January 1977 and March 1978 contamination map data were on the order of 30 and 24%. All the above figures are considered optimistic. A few years after the accident, mean TCDD half-life in soil appeared to be 9.1y (t1/2-95% CLs, 6.2-17y).     

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Guppies (Poecilia reticulatus Peters)

Summary Exposure of guppies to 0.1, 1.0, or 10.0 ppb TCDD for 120 hours caused complete mortality in the next 32, 21, and 30 days, respectively. Duration of survival was significantly and positively correlated with body length. The concentrations of TCDD used in these tests were considerably greater than expected to occur in forest streams after aerial application of 2,4,5-T. The threshold-response level for TCDD in fish has not been reported.     

Biochemical and toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) congeners in female rats

The capability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)² and six congeners to induce toxic and biochemical changes in rats was investigated. In addition to TCDD, the following compounds were administered at a dose of 40 or 400 g/kg/day for three days P.O.: 2,7-dichlorodibenzo-p-dioxin (DCDD); 1,2,4-trichlorodibenzo-p-dioxin (TrCDD); 1,2,3,4-tetrachlorodibenzo-p-dioxin; l,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; 3,3,4,4,5-pentachlorobiphenyl (PCB); and 2,2,4,4,5,5-hexachlorobiphenyl (HCB). Six days after treatment the animals were killed. Lipid peroxidation and glutathione peroxidase (GSH-PX) activity were determined in liver and kidney. Hepatic aryl hydrocarbon hydroxylase (AHH) activity was determined 48 hr following the administration of 400 g/kg of each congener or 40 g/kg of TCDD. With the exception of PCB and TCDD, the other congeners produced no toxic or biochemical changes at the doses given as determined by the above parameters. PCB (400 g/kg) resulted in a 4-fold increase in lipid peroxidation and a 69% decrease in GSH-PX activity. These results were comparable to the effects of a 40 g/kg dose of TCDD. PCB treatment resulted in a 80% decrease in thymus weight, and a 3.8-fold increase in AHH activity which were comparable to the effects of TCDD. A correlation appears to exist between the ability to induce hepatic AHH activity, enhance lipid peroxidation. inhibit GSH-PX activity, and decrease body and thymus weights.Abbreviations include TCDD 2,7-dichlorodibenzo-p-dioxin - DCDD 1,2,4-trichlorodibenzo-p-dioxin - TrCDD 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin - OCDD 3,3,4,4,5-pentachlorobiphenyl - PCB 2,2,4,4,5,5-hexachlorobiphenyl - HCB malondialdehyde - MDA aryl hydrocarbon hydroxylase - AHH glutathione peroxidase - GSH-PX 8-aminolevulinic acid - ALA structure-activity relations     

Alteration of rat hepatic plasma membrane functions by 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)

In vivo administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to rats produced significant alterations in Na-K, Ca, Mg ATPase and protein kinase activity, and receptor binding activity to insulin, concanavalin A, glucagon and epidermal growth factor in the canaliculi-rich plasma membrane fraction of the hepatocytes. Some of the changes are dose-related, and generally follow the time course of the sign of TCDD poisoning in the rat (e.g., the loss in body weight). Such TCDD-induced changes in membrane proteins and subsequent alteration in membrane functions appear to be extensive.     

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).     

Decontamination of human skin exposed to 2,3,7,8-tetrachlorodibenzo-p-Dioxin (TCDD) in vitro.

Human post-mortem skin was exposed in vitro to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 32 degrees C, under controlled humidity. In one-half of the samples, damage to the surface of the skin was simulated by stripping of the stratum corneum. After incubation with TCDD for 100 min, four different decontamination protocols were performed: (1) the sample was wiped with dry, adsorbent material (cotton balls); (2) a 10-min topical treatment with mineral oil was followed by dry wiping with cotton balls; (3) a 10-min topical treatment with mineral oil was followed by wiping with acetone-soaked cotton balls; and (4) the sample was washed with water and soap. After decontamination, skin samples were incubated (up to 300 min) again at 32 degrees C. One set of both intact and stripped TCDD-exposed skin samples was incubated for 300 min--absent decontamination--and was used as a control. Mineral oil treatment and acetone wipes, or water and soap, were effective in reducing (i.e., about two-fold) the amount of TCDD in the stratum corneum of intact skin. Mineral oil plus dry wipes reduced the amount of TCDD in the stratum corneum by about one-third, whereas dry wiping alone was ineffective. All protocols, however, were similarly effective in reducing the amount of TCDD in the epidermis and upper dermis; TCDD concentrations were decreased locally by factors of up to ten. In the lower dermis, a minimal effect of the decontamination procedures was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Flow cytometric analysis of lymphocyte subpopulations in bronchoalveolar lavage fluid after repeated ozone exposure

As known from studies in animal and human subjects, ozone can exert effects on the immune response including allergic sensitisation and allergen responsiveness. The objective of the present study was to assess the changes in lymphocyte subsets in bronchoalveolar lavage fluid (BALF) after single and repeated ozone exposures. Twenty-three healthy subjects underwent single exposures to 200 ppb ozone or filtered air (FA), as well as repeated exposures to 200 ppb ozone on four consecutive days, each during 4 h of intermittent exercise. Bronchoalveolar lavage was performed 20 h after the single exposure or the last of the repeated exposures. Lymphocytes were identified by sideward scatter and CD45 expression, and their subsets by eight different panels of antibodies. Checksums were calculated to assess the validity of the results. The percentage and the absolute number of lymphocytes, mostly comprising T-lymphocytes (CD2⁺; overall mean 98.8%), increased after single (P < 0.05; each), but not after repeated ozone exposure, compared with FA (7.4 vs 5.8 vs 6.5%; 680 vs 419 vs 301 × 10³). In addition, we observed small but statistically significant changes in the proportions of lymphocyte subpopulations. The percentage of CD4⁺ lymphocytes increased after single (P < 0.05) and repeated ozone exposure (P < 0.01), whereas the percentage of CD8⁺ cells decreased after repeated exposure (P < 0.05). The proportion of activated lymphocytes (CD25⁺) was elevated after repeated, compared with single, ozone exposure (P < 0.01), and the percentages of natural killer (NK) cells were decreased after both single (P < 0.05) and repeated (P < 0.01) exposures. Our data suggest that single but not repeated ozone exposures cause a change in absolute numbers of lymphocytes in BALF, whereas the proportions of lymphocyte subsets are affected by single as well as repeated exposures. Received: 21 June 2000 / Accepted: 10 November 2000     

Toxicity reference values for mink exposed to 2,3,7,8-tetrachlodibenzo-p-dioxin (TCDD) equivalents (TEQs)

Dietary and tissue residue-based toxicity reference values (TRVs) were derived for mink from the published results of studies in which mink were exposed to polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), or related compounds. Because the primary mechanism of toxic action at the least concentration for these compounds is related to activation of the aryl hydrocarbon receptor (AhR), TRVs were described on the basis of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents (TEQ). Each published study was critically reviewed for its usefulness in deriving a TRV based on the following criteria: (1) close relatedness of the test species to the wildlife receptor of concern (only mink studies were reviewed in this paper); (2) chronic duration of exposure which included sensitive life stages to evaluate potential developmental and reproductive effects; (3) measurement of ecologically relevant endpoints; (4) availability of congener-specific data to calculate TEQ concentrations; and (5) minimal impact of co-contaminants. Dietary TRVs for mink exposed to TEQ ranged from 12.1 to 56.6 ng TEQ/kg feed (wet weight) for the no observable adverse effect level (NOAEL) and from 50.4 to 242 ng TEQ/kg feed (wet weight) for the lowest observable adverse effect level (LOAEL). TRVs based on tissue residue concentrations ranged from 50.2 to 77.8 ng TEQ/kg liver (wet weight) for the no observable adverse effect concentration (NOAEC) and the value was 189 ng TEQ/kg liver (wet weight) for the lowest observable adverse effect concentration (LOAEC). Selection of a TRV should be based on studies of compounds that are most similar to those at a site of interest. In particular, it was determined that the effects of PCDFs could not be accurately predicted from the use of TEQ-based TRVs developed from studies of PCDDs or PCBs. Risk assessors should be aware that exceedance of these TRVs would not necessarily be expected to lead to ecologically relevant adverse effects because of the inherently conservative assumptions made in the TRV derivation process.     

Xenoestrogen modulation of the immune system: effects of dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are complex organic compounds that are frequently found in the environment as a result of agricultural and industrial activities. Both compounds have substantial immune system and endocrine system disrupting activity, acting as estrogen agonists or antagonists (xenoestrogens). Research has demonstrated that exposure to xenoestrogens can result in body weight loss, developmental abnormalities, thymic atrophy, carcinogenesis, and tissue-specific hypoplastic and hyperplastic responses. Although several studies have reported significant adverse effects of these compounds on the endocrine system, very few investigations have focused on the specific mechanisms of action on the immune system. This paper reviews the cellular and molecular mechanisms of DDT- and TCDD-induced toxicity on the endocrine and immune systems, and explores their potential impact on the pathogenesis of immune disease.     

Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) levels and thyroid function in Air Force veterans of the Vietnam War

PURPOSE: We assessed potential health effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentration in serum on thyroid function in US Air Force veterans involved in Operation Ranch Hand, the unit responsible for the aerial spraying of herbicides, including TCDD-contaminated Agent Orange, during the Vietnam War from 1962 to 1971. Other Air Force veterans who were not involved with spraying herbicides were included as Comparisons. METHODS: We analyzed thyroxine (total T4), thyroid stimulating hormone (TSH), triiodothyronin percent uptake (T3% uptake), the free thyroxine index (FTI), and thyroid diseases against serum TCDD levels. Data was available for 1,009 Ranch Hand and 1,429 Comparison veterans compliant to any of five examinations in 1982, 1985, 1987, 1992, and 1997. Each veteran was assigned to one of four exposure categories based on serum TCDD levels, named Comparison, Ranch Hand Background, Ranch Hand Low Elevated, and Ranch Hand High Elevated. RESULTS: Cross-sectional analyses found statistically significantly increased TSH means at the 1985 and 1987 examinations in the High category and a significant increasing trend across the three Ranch Hand TCDD categories in 1982, 1985, 1987 and 1992. A repeated-measures analysis found significantly increased TSH means in the High TCDD category. We found no significant relation between the occurrence of thyroid disease and TCDD category. CONCLUSIONS: These findings suggest that TCDD affects thyroid hormone metabolism and function in Ranch Hand veterans. Further follow-up will be necessary to understand the relation, if any, between thyroid disease and TCDD levels.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the lactating rat on maternal and neonatal vitamin A status

Female Sprague-Dawley rats were given a single oral dose of 10 micrograms TCDD/kg body wt after delivery. Pups were killed on postnatal day (PND) 0, 2, 4, 8, or 16. Dams and remaining weanlings were killed on PND 22 and 32, respectively. Thymus weight was lower in dams exposed to TCDD than in controls, whereas no differences in body weight or relative liver weight were found. The total amount and the concentration of vitamin A were lower in the liver but higher in the kidneys and in serum of TCDD-treated dams than in controls. TCDD-exposed weanlings showed lower weight gain, liver enlargement and thymus atrophy compared to controls. Growth reduction became more pronounced with time, liver enlargement was at its peak on PND 8 and thymus atrophy was most pronounced on PND 16, although all three effects persisted throughout the study. The total amount of vitamin A increased at a similar rate in control and TCDD-exposed weanlings throughout lactation. When the young started to eat pelleted diet there was a pronounced increase in hepatic vitamin A content. Between PND 16 and 32 controls increased their hepatic vitamin A content 21-fold, compared to 12-fold in TCDD-exposed offspring. The hepatic stores of TCDD-treated animals reached 45% of the stores of control pups on PND 32. From PND 8 renal vitamin A was significantly higher in the TCDD-exposed young than in the controls. At PND 32 TCDD-exposed weanlings had six times more renal vitamin A than controls.