ISSN:0265-203X    

DOI:10.1080/713810655

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

The present situation with respect to the exposure of the general human population to PCDDs, PCDFs and (dioxin-like) PCBs and specific issues that should be taken into consideration for a risk assessment of these exposures have been summarized. The information is based on studies performed in The Netherlands and Germany in the last 10 years. Additional data have been collected through a literature search and through many contacts with researchers and national authorities. The most important route for human exposure to PCDDs, PCDFs and (dioxin-like) PCBs is food consumption contributing over 90% of total exposure, with products of animal origin and fish making the greatest contribution to this exposure. The dietary intake of PCDDs and PCDFs by the general population of industrialized countries is on average 1–3 picograms of (i)-TEQ per kilogram body weight per day. If the contribution of dioxin-like PCBs are also considered, the daily TEQ intake can be a factor of two to three higher. Special consumption habits and consumption of highly contaminated foodstuffs may lead to lower and higher TEQ intakes. In general, TEQ intake increases during childhood and stabilizes in adults of about 20 years of age. However, when normalized by body weight exposure is found to decrease with childhood age due to increasing body weight. Exposure has been shown to have fallen over time in all countries where data are available. Countries that started to implement measures to reduce dioxin emissions in the late 1980s, such as The Netherlands, United Kingdom and Germany, clearly show decreasing PCDD/PCDF and PCB levels in food and consequently a significantly lower dietary intake of these compounds by almost a factor of 2 within the past 7 years.

ISSN:0265-203X    

DOI:10.1080/026520300283324

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

The Ah receptor mediates the toxicological responses of 2,3,7,8-TCDD and related compounds. Receptor-deficient animals were shown to be resistant to the toxic effects of dioxin, although there is also evidence for the existence of a receptor-independent pathway for dioxin-induced toxicity. In the cytosol the receptor is present in a non-activated ligand binding conformation. Association with Arnt in the nucleus turns the receptor complex into a ligand activated form. The physiological role of the receptor is not yet understood; however, the conservation of the receptor in a wide range of animal species (including humans) suggests a fundamental role in cellular physiology.

ISSN:0265-203X    

DOI:10.1080/026520300283333

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

The toxicokinetic determinants of dioxin and related chemicals depend on three major properties: lipophilicity, metabolism, and binding to CYP1A2 in the liver. The induction of CYP1A2 is partially under the control of the aryl hydrocarbon receptor (AhR). Lipophilicity increases with more chlorination and controls absorption and tissue partitioning. Metabolism is the rate limiting step for elimination. Induction of CYP1A2 leads to hepatic sequestration of TCDD. Binding to this inducible hepatic protein results in non-linear dosedependent tissue distribution: with increasing doses, the relative concentration in extra-hepatic tissues decreases while that in liver increases. The induction of this protein occurs in both animals and humans and results in an increase in the liver to fat ratio of these compounds. Humans have similar sensitivities to rodents for dioxin-like compounds when using tissue concentration (from in vitro studies), body burden, average lifetime serum lipid concentration, or lifetime area-under-the-curve concentration based on both low dose (biochemical) and high dose (cancer) driven endpoints. To reach the same tissue concentration in humans as rodents however, humans need a lower daily intake than rodents based on differences in pharmacokinetic behaviour. This clearly indicates that physiologically based pharmacokinetic models should be explored for the estimation of the daily intake of dioxin-like compounds in humans based on tissue dose levels or derivatives of those.

ISSN:0265-203X    

DOI:10.1080/026520300283342

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

Exposure to TCDD and related chemicals leads to a plethora of effects in multiple species, tissues, and stages of development. Responses range from relatively simple biochemical alterations through overtly toxic responses, including lethality. The spectrum of effects shows some species variability, but many effects are seen in multiple wildlife, domestic, and laboratory species, ranging from fish through birds and mammals. The same responses can be generated regardless of the route of exposure, although the administered dose may vary. The body burden appears to be the most appropriate dosimetric. Many of the effects often attributed to TCDD are associated with relatively high doses: lethality, wasting, lymphoid and gonadal atrophy, chloracne, hepatotoxicity, adult neurotoxicity, and cardiotoxicity. Changes in multiple endocrine and growth factor sytems have been reported in a manner which is tissue, sex, and age-dependent. The most sensitive adverse effects observed in multiple species appear to be developmental, including effects on the developing immune, nervous, and reproductive systems. Such effects have been observed at maternal body burdens in the range of 30–80 ng/kg in both non-human primates and rodents. Biochemical effects on cytokine expression and metabolizing enzymes occur at body burdens which are within a factor of ten of the clearly adverse developmental responses. Thus, effects on the immune system, learning, and the developing reproductive system of multiple animals occur at body burdens which are close to those present in the background human population.

ISSN:0265-203X    

DOI:10.1080/026520300283351

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

Dioxin and certain structurally related compounds increase the incidence of liver neoplasms in rodents upon chronic bioassay. Short-term studies indicate the lack of direct DNA-damaging effects including covalent binding to DNA; however, secondary mechanisms may be important in the observed carcinogenicity as these chemicals affect a number of pathways necessary for maintenance of normal growth control and differentiation status. Studies with TCDD in the mouse skin support a lack of initiating activity but an ability to promote the growth of previously initiated lesions indicative of a promoting agent. Mouse skin tumour promotion studies indicate that Ah receptor activation may be involved in promotion by TCDD and selected structurally related compounds. While the mechanism of carcinogenicity induced by TCDD is unknown, the processes involved have a no-effect level, which in the rat liver is at an exposure level below 10 ng TCDD/kg/ day. At least for the rodent liver, the relative effective dose for cytochrome P450 induction is not a good indicator of promotion potency. Studies on liver tumour promotion in the female rat liver support a nongenotoxic mechanism for the induction of neoplasms by TCDD. The ability of TCDD to enhance proliferation and inhibit apoptotic processes in focal hepatic lesions further supports an indirect mechanism of carcinogenicity.

ISSN:0265-203X    

DOI:10.1080/026520300283360

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

In 1949, the first descriptions of human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) contaminated chemicals were reported after a trichlorophenol reactor explosion in Nitro, West Virginia, USA. Reported non-cancer health effects included a range of conditions affecting most systems. Additional reports of the health consequences of exposure continued through the remainder of the century. The majority of effects have been reported among highly exposed groups including occupational populations, such as chemical production workers, pesticide applicators, and individuals who handled or were exposed to materials treated with 2,3,7,8-TCDD-contaminated pesticides, and among residents of communities contaminated with tainted waste oil (Missouri, USA) and industrial e uent (Seveso, Italy). For only six exposed populations were biological measurements of 2,3,7,8-TCDD contaminated collected and used to examine the relationship between non-cancer health effects and exposure. Of the many non-cancer health effects thought to be associated with 2,3,7,8-TCDD exposure, only chloracne, elevations in GGT and triglyceride levels, and alterations in FSH and LH were related to serum 2,3,7,8-TCDD levels. Mortality from cardiovascular diseases also appeared to be elevated among cohorts of exposed chemical workers and Seveso residents. Continued surveillance of the health of exposed populations will be useful in identifying the long-term effects of both high and low 2,3,7,8-TCDD exposure.

ISSN:0265-203X    

DOI:10.1080/026520300283379

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

The epidemiological evidence from the most highly 2,3,7,8-TCDD-exposed cohorts studied produces the strongest evidence of increased risks for all cancer combined, along with less strong evidence of increased risks for cancer of particular sites such as non-Hodgkin lymphoma, soft-tissue sarcoma and lung cancer. The relative risk for all cancer combined in the most highly exposed and longer-latency sub-cohorts is 1.4. While this relative risk is not likely to be explained by confounding, this possibility cannot be excluded. It should be borne in mind that the general population is exposed to 2–3 orders of magnitude lower levels of TCDD than those experienced by the equivalent lifetime dose in the industrial populations examined or the population of Seveso.

ISSN:0265-203X    

DOI:10.1080/026520300283388

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

Global contamination by a variety of anthropogenic persistent organic chemicals, such as dioxins and PCBs, has resulted in human exposure throughout all phases of development. Detectable concentrations of PCBs and dioxins have been found in amniotic fluid, placenta and foetal tissue samples while infants who are breast-fed can obtain blood levels greater than those of their mother's. In two separate food poisoning episodes where infants were exposed in utero to elevated levels of heat-degraded PCBs (PCBs, PCQs, PCDFs), a variety of adverse mental and physical developmental abnormalities have been observed. In additional human cohorts where exposure could be considered as environmental or background, more subtle effects, including lower birth weights, alterations in thyroid hormones and lymphocyte subpopulations and detriments in neurological development, have been consistently seen. In most instances, negative associations were made between in utero exposure to contaminants compared with lactational. Although the observed neurodevelopmental deficits have been described as subtle, there could be unknown consequences related to future intellectual functionality. Current regulatory efforts should focus on identification and control of environment and food chain contamination as in utero exposure is a direct consequence of the accumulated maternal body burdens.

ISSN:0265-203X    

DOI:10.1080/026520300283397

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor

摘要:

Conducting a dose-response analysis for an environmental contaminant requires a careful evaluation of most of the available data focusing on both the magnitude of the effect and the possible ranges of dose-response shapes which fit the data. This paper calculates potency values (1% response exposures) for human and animal data on cancer, non-cancer and biological effect endpoints for TCDD and finds that a reasonable estimate for 1% excess cancer would be between 1 and 50 pg/kg/day. The paper also evaluates the adequacy of linear and non-linear models for fitting these data and concludes that the assumption of a threshold dose-response is not fully supported by these data.

ISSN:0265-203X    

DOI:10.1080/026520300283405

出版商:Taylor & Francis Group    

年代:2000

数据来源: Taylor