Health Risks from Dioxin and Related Compounds Evaluation of the EPA Reassessment (2006) / Chapter Skim
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6 Noncancer End Points
6 Noncancer End Points
Pages 144-174
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From page 144... ...
and Related Compounds (EPA 2003a, Part I; 2003b, Part II; 2003c, Part III) is collectively referred to as the Reassessment.
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From page 145... ...
; "other in vivo and in vitro data, however, suggest that non-AHR (aromatic hydrocarbon receptor) -mediated mechanisms may also play
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From page 146... ...
Nevertheless, because of extensive animal work, the database is sufficient to indicate that immune effects could occur in the human population from exposure to TCDD and related compounds at some dose level. At present, it is EPA's scientific judgment that TCDD and related compounds should be regarded as nonspecific immunosuppressants and immunotoxicants until better data to inform judgment are available" (p.
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From page 147... ...
Because in vivo immunotoxicity data for 2,7-dibenzo-pdioxin are available only in the mouse, it is unclear whether the unexpected potency of this congener occurs in other animal species and humans. A second example pertains to certain halogenated aromatic hydrocarbons (HAHs)
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From page 148... ...
The most obvious reason for the inconclusive findings in human studies is that, in many cases, a very small number of subjects were evaluated, their primary exposures were often long before measurement of immune end points and concentrations of TCDD and related compounds, and the nature of those exposures were often unclear. Furthermore, obtaining an accurate estimate of the level of exposure through back-extrapolation from current body levels may be more complex than simply using a single half-life throughout.
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From page 149... ...
. The Dutch study measured the major PCB congeners in plasma in the mother and the newborn and all TCDD and related compounds in maternal breast milk 10 days and 3 months postpartum (Feeley 1995)
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A second recent report (Van den Heuvel et al.
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1996) and its developmental immunotoxicological risk characterization on a single rat study (Gehrs and Smialowicz 1999)
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(1994) (the other three studies identified in Table A-1 and used for risk characterization of the adult immune system)
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From page 153... ...
Collectively, in light of the large database showing that these compounds are immunotoxic in laboratory animal studies together with sparse human data, EPA is being prudent in judging TCDD, other dioxins, and DLCs to be potential human immunotoxicants in the absence of more definitive human data. · EPA's conclusion that TCDD, other dioxins, and DLCs are immunotoxic at "some dose level" by itself is inadequate.
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From page 154... ...
Likewise, EPA should provide a clear scientific rationale for selecting ED01 as a benchmark dose. · Considerations of the Burleson et al.
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From page 155... ...
For example, the WHO 1998 TEQs appear to be 2.5fold higher (Van den Berg et al.
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From page 156... ...
1992) and imply a TEF based on female reproductive effects of 0.2 for PeCDD and 0.04 for HxCDD, which differ from the WHO report in which a TEF of 1 was given for PeCDD (Van den Berg et al.
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From page 157... ...
Exposure of adult female rats to PCDDs disrupted estrous cycles, delayed ovulation, and lowered ovarian weights (Li et al. 1995a; Cummings et al.
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From page 158... ...
. However, another study reported an initial inhibition of estradiol in human luteinized granulosa cells that was followed by increased estradiol accumulation at 36 and 48 hours (Heimler et al.
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. TCDD is well known to inhibit estradiol-induced PR in the breast cancer cell line MCF-7 through an AHR-mediated mechanism (Harper et al.
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From page 160... ...
Developing mice exhibited altered vascular architecture, including massive portosystemic shunting due to a patent ductus venosus, resulting in reduced blood flow to the liver and hence reduced hepatocyte size and liver mass. This failure of the ductus venosus to close in Ahr-/- mice was subsequently associated with major hepatic veins failing to decrease in size, as observed in wild-type mice, which may result in increased blood pressure or a failure in vasoconstriction (Lahvis et al.
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From page 161... ...
and describes to a lesser extent various other noncancer consequences, including hepatic, thyroid, and cardiovascular effects observed in animals other than humans (Part II, Chapter 7, part B)
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5-15 to 5-16) because "all four manifestations of developmental toxicity (reduced viability, structural alterations, growth retardation, and functional alterations)
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; (3) "many epidemiological studies are hampered by small sample size, and in many cases the actual amounts of TCDD and related compounds in human tissues were not examined" (Part II, p.
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From page 164... ...
, although the formal criteria for defining human hazard in the context of these noncancer end points are not defined precisely in the Reassessment. Further, although the Reassessment acknowledges that "some have argued that in the absence of better human data, deducing that a spectrum of noncancer effects will occur in humans overstates the science" (Part III, p.
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From page 165... ...
1997) , concluding that "the human data offer some evidence of alterations in male reproductive hormone levels associated with substantial occupational exposure to 2,3,7,8TCDD" (Part II, p.
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From page 166... ...
(2002a) , chose to describe their findings as a "doubled, nonsignificant risk for endometriosis among women with serum TCDD levels of 100 ppt or higher, but no clear dose response." Finally, in a recent review of the nonhuman primate and the human data assessing the relationship between TCDD exposure and endometriosis Guo concluded that "there are no solid, credible data available at this moment to support the hypothesis that dioxin exposure may lead to the development of endometriosis" (Guo 2004)
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From page 167... ...
. For the state of available information in 2000, the Reassessment describes adequately the observed effects of TCDD exposure on offspring sex ratio (Part II, sections 7.13.12.7, 7.15.3.4.8)
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From page 168... ...
and formula-fed infants (primarily exposed in utero with background postnatal exposure) , including no overall differences in global cognitive index, memory, or motor performance, except when children from "less optimal homes" were analyzed separately.
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From page 169... ...
Ranch Hands in both the low dioxin category and the low and high dioxin categories combined were found to have a lower mean systolic blood pressure. Similarly, a smaller percentage of Ranch Hands in both the low dioxin category and the low and high dioxin categories combined had an abnormally high systolic blood pressure" (p.
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From page 170... ...
C-peptide and time to diabetes onset decreased as initial dioxin increased." The risk of diabetes requiring insulin control was increased in the Ranch Hand high-dioxin category. An increase in the risk of diabetes requiring oral hypoglycemic or insulin control was observed as 1987 dioxin levels increased.
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From page 171... ...
Follow-up of the Dutch children's cohort has now been carried out for more than a decade, and changes in thyroid status in this cohort have not been reported, although it is unclear whether they were in fact thoroughly assessed. The text in the Reassessment does include lengthy hypothetical discussions (Part III, 2.2.1.3 and Part III, 2.2.6.2)
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From page 172... ...
The most recent Ranch Hand follow-up showed no relationship between TCDD exposures and total high-density-lipoprotein cholesterol, although ranch hands had an increased percentage of individuals with increased triglyceride values (DOD 2005, pp.
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From page 173... ...
· In reference to human disease risks, the overall conclusions about noncancer risks due to TCDD exposure are, in general, cautiously stated, and the uncertainty of suspected relationships is acknowledged. Nonetheless, the limitations of specific human studies are not uniformly addressed, and the broad 95% CIs accompanying some reported statistically significant effects are not discussed in the context of the uncertainty that these broad confidence limits imply.
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From page 174... ...
The quality of the available evidence should be reported, and the strength or weakness of a presumptive association should be classified according to currently accepted criteria for levels of evidence. Animal studies have shown that TCDD can cause a variety of noncancer effects.
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