July 01, 2005

Dioxinas e cancro

2,3,7,8-tetrachlordibenzo-p-doxin (TCDD) would not have been designated as a Group 1 carcinogen by IARC had there not
been a change in the criteria used for inclusion in this category. Furthermore, there is no precedent for indicating, as did IARC, that
a single chemical acts as a pluripotential carcinogen by modestly increasing human risk for all cancer while not increasing the risk
for any single cancer at least moderately. IARC moved TCDD to Group 1 based on mechanistic considerations focusing on the Ah
receptor. However, while occupancy of the Ah receptor by TCDD may be necessary for its toxicity, it is not sufficient for toxicity or
for potential carcinogenicity. Animal evidence relating TCDD exposure to cancer is much stronger than that for humans. However,
the large inter-species variation in the relevant dose–response slopes severely limits generalizations from animals to humans. The
epidemiologic studies of occupational exposures, pesticide applicators, and community exposures following industrial accidents,
notably Seveso, have generated overall relative risks of all cancer of about 1.0. Only case-control studies of soft-tissue sarcoma and
non-Hodgkins lymphoma, all by the same investigator, reported elevated risk from TCDD exposure. However, these results have
not been replicated. The representation that a chemical compound (TCDD) would be a late-stage carcinogen for all types of cancer
has no precedent and lacks biological foundation. Virtually all late-stage or promoting carcinogens (e.g., hepatitis-C virus, asbestos,
and estrogens) cause a very limited number of forms of cancer. The exposure–response meta-analysis of TCDD and cancer developed
by the United States Environmental Protection Agency (USEPA) is seriously compromised by its failure to adequately fit
the data. The studies used by the USEPA also likely underestimate TCDD body burdens and may be confounded by smoking and
other occupational exposures. Furthermore, the use of a linear dose–response model by the USEPA is scientifically unjustified since
the underlying model of TCDD as a human carcinogen is based primarily on its supposed receptor-mediated, non-genotoxic (or
promotional) mode of action. There are few examples of an agent being suspected as a human carcinogen for decades and then
eventually moving into the category of ‘‘known’’ human carcinogens. In contrast, there are hundreds of compounds that remain for
decades on lists of ‘‘suspected’’ human carcinogens despite the lack of confirming evidence. The long-term accumulation of negative,
weak, and inconsistent findings suggests that TCDD eventually will be recognized as not carcinogenic for humans.
 2003 Elsevier Inc. All rights reserved.

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Discursão - acumulação tecidos (cont.)

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discursão - dioxinas acumulação tecidos

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dixinas - acumulação nos tecidos humanos

Polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofuran and dioxin-like polychlorinated biphenyl concentrations
in human liver, kidney, fat, blood, muscle, richly perfused tissue (brain, lung etc.) and skin were simulated to
assess the health risk for Japanese fetuses. A 40-year time course of dioxin accumulation via food ingestion was
simulated using a physiologically based pharmacokinetic (PBPK) model. In richly perfused tissue, the concentration
estimated by the PBPK model showed better agreement with measured concentrations than that calculated by the onecompartment
model. Fetal dioxin concentration was simulated based on the assumption that the fetal concentration
was almost equal to the concentration in the mothers richly perfused tissue. To assess the reproductive risk, the estimated
concentration in human fetus was compared with that in rat fetus in which reproductive function showed signs
of alteration by 2,3,7,8-TCDD in previous reports [Toxicol. Appl. Pharmacol. 114 (1992) 118; 146 (1997) 11; Toxicol.
Sci. 53 (2000) 411; 57 (2000) 275]. The present daily intake of 2,3,7,8-TCDD is approximately 1/50 of the amount that
leads to possible reproductive toxicity in the next generation. However, when 29 kinds of dioxin congeners are considered,
the present level is 1/5 of the hazardous levels. For species extrapolation of dioxin risk, further study on tissue
concentration versus toxicity is required

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dioxinas - discurssão

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In response to aggressive attempts to control dioxin emissions over the last 35 years, human exposures to dioxins from the environment
have declined significantly. The primary source of human exposure to dioxins at present is food. The sources of dioxins in
food are not well understood and are probably varied. Data on the levels of dioxins measured in various foods for samples collected
from 2000 to 2002 have recently been released by the US Food and Drug Administration as part of its Total Diet Study. Data on
samples collected in 1999, and released in 2002, are also available. Based on those data and on the US Department of Agricultures
most recent food consumption survey (1994–1996 & 1998 Continuing Survey of Food Intakes by Individuals), estimates of dioxin
intake for the total US population and for three age groups of children were obtained. Results show that the most recent mean
dietary exposures for all groups are below 2 pg TEQ/kg BW/day, the tolerable daily intake established for dioxins by the World
Health Organization. Between 1999 and 2002 mean dioxin intakes from food appear to have decreased, but when estimates are
adjusted based on a standardized limit of detection and evaluating only those {congener · food} combinations common to all 4
years, no trend is apparent. When dioxin concentrations below the limit of detection are represented by one-half the limit, approximately
5% of the intake estimates for 2-year-olds and 1% of the intake estimates for 6-year-olds exceed the tolerable daily intake by
about 10%, although such upper-percentile estimates should not be equated with excess risk. When non-detectable dioxin values are
set to zero (i.e., when only dioxin values actually measured are used), only 1% of intake estimates exceed the tolerable daily intake
for 2-year-olds. As expected, about 50% of daily dietary dioxin intake by the total US population is attributable to meat and dairy
products, based on the same food group classifications used by the National Academy of Sciences Committee on the Implications of
Dioxin in the Food Supply. This information may be useful for targeting future risk management activities.
 2005 Elsevier Ltd. All rights reserved.

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