Hormonally Active Agents in the Environment (1999) / Chapter Skim
Currently Skimming:
4 Dosimetry
4 Dosimetry
Pages 82-118
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 82... ...
; or as the amount reaching and binding with a receptor or other target molecule (the biologically significant dose)
|
From page 83... ...
The accumulation of HAAs is determined by the rate and efficiency of several processes: absorption, or partitioning, of a bioavailable chemical between the external medium and the cell layers first exposed; transport in blood; partitioning between blood and body lipids or target cells; metabolism of the chemical; and excretion and elimination from the body. In this chapter, these processes are summarized, and examples illustrate the complexities as well as the extent of our knowledge in these areas.
|
From page 84... ...
For example, the metabolism rates of PCB congeners are strongly influenced by the presence of vicinal, unsubstituted carbons at the meta or para position (Chen et al. 1982; Matthews and Dedrick 1984~.
|
From page 85... ...
1986 Total PCBsb,C Rhesus monkey Blood 0.3-7.6 yr Mes et al. 1995 Adelie penguin Multiple 270 d Subramanian et al.
|
From page 86... ...
, and some PCB congeners can pass through the skin of mammals, including humans and can be taken up from the water by fish (Bruggeman et al. 1981; Reifenrath et al.
|
From page 87... ...
However, soy-based milk substitutes can deliver much greater amounts of phytoestrogens than are found in either bovine or human milk. Plasma concentrations of genistein measured in infants fed soy-based formulas averaged 684 ng/mL, a much greater amount than those found in infants fed
|
From page 89... ...
89 ca 4= V, Do Do ca sit ~ 11 ~ o o Do V ~ of of of ~ of of of En ~ ~ ~ ~ ~ ~ Em t.4 t.4 t,.4 t,.4 t,.4 t,.4 ~4 o o ~ ~ Do ~ ~ ···O ···m)
|
From page 90... ...
1994) , the concentrations of 23 PCB congeners and of DDT and other pesticides were examined in human milk.
|
From page 91... ...
There was a significant correlation between the concentration of total DDTs in subcutaneous fat and milk fat (r = 0.963) , in subcutaneous fat and maternal serum fat (r = 0.843)
|
From page 92... ...
(1994) described similar time- and dose-dependent changes in the residues of the same PCB congeners in liver, adipose tissue, and blood of rats.
|
From page 93... ...
(1997) reported that the observed partitioning between blood and adipose tissue was similar to the partitioning in PB-PK models and that there was a two- to three-fold difference in the partitioning between different PCB congeners, which was consistent with the model.
|
From page 94... ...
Persistence and organ distribution could influence extrapolations of dosage from one species to another for example, for TCDD but these have not been adequately determined in enough species (Whysner and Williams 1996~. A1though knowledge of distribution to different tissues is important to interpretations regarding toxicity, comparing the effects of some compounds on the basis of the total body burden could reveal similarities not evident when concentrations in individual tissues are used to compare responses between species.
|
From page 95... ...
Once inside a target cell, a steroid presumably dissociates from the plasma protein and becomes available for binding to specific intracellular receptors because of the lower binding affinity of steroids for plasma proteins relative to intracellular receptors. Siiteri et al.
|
From page 96... ...
1998~. In humans, total serum estradiol concentration is approximately 100-fold greater in fetuses than it is in adults; the free serum estradiol concentration in human adults and fetuses is similar (Nagel et al.
|
From page 97... ...
Only two PCB congeners were detected in brain tissue, where total PCB content was only about 1 % of that measured in the blubber. The basis of tissuespecific accumulation of PCB congeners, with the patterns of PCB congeners in liver and brain differing from those in blood and blubber, is not known.
|
From page 98... ...
1993~. Cellular localization of proteins involved in HAA effects could help to identify sensitive target cells.
|
From page 99... ...
Fatty tissues in vertebrates include adipose tissue, liver, gonads, neural tissue, brain, and, in some fish, muscle. Adipose tissue in most vertebrates acts as a depot for organic xenobiotics.
|
From page 100... ...
pathways. Inferences regarding HAA effects and dose-response relationships can be weakened by the failure to distinguish between these mechanisms.
|
From page 101... ...
1982~. Metabolism-Modifying Factors The capacity to metabolize steroids and HAAs in target and nontarget organs can change as a result of exposure to HAAs and to chemicals that affect enzymes that metabolize HAAs or steroids.
|
From page 102... ...
Steroid synthesis involves numerous steps leading to the active hormones. The steroid synthetic enzymes include CYPll (side-chain-cleavage enzyme)
|
From page 103... ...
The effects of HAAs on CYP enzymes in those target organs could be more directly significant. Extrahepatic Enzymes and HAA Effects The complement of enzymes that metabolize HAAs can strongly influence the susceptibility of the cell to the effects of these compounds.
|
From page 104... ...
The same CYP enzymes were detected also with antibodies, and there were distinct patterns of expression associated with age, reproductive status, and lactation. Recent studies of the mammary gland have focused on a relatively recently discovered enzyme, CYPlBl, which activates polycyclic aromatic hydrocarbon (PAM)
|
From page 105... ...
That possibility is suggested by studies of placental CYP2E1, which metabolizes alcohol, and fetal alcohol syndrome (Rasheed et al.1997~. Fetal alcohol syndrome might result from acetaldehyde produced from alcohol in the fetus (Holownia et al.
|
From page 106... ...
A role for estradiol metabolism in breast cancer has been suggested repeatedly (Yager and Liehr 1996~. The formation of 160c-hydroxy-E2, a metabolite of estradiol, has been suggested by some investigators to be a risk factor in human breast cancer (Bradlow et al.
|
From page 107... ...
examined the ability of 4OH-E2 and 2-OH-E2 to cause oxidative damage of DNA and reported that 4-OHE2 caused greater damage than did 2-OH-E2, consistent with a more-rapid redox cycling of the 4-OH-E2. Reactive oxygen species can damage DNA, but they also can alter various signal transduction pathways involving cell proliferation, notably in early development (Ozolins and Hales 1997~.
|
From page 108... ...
1992~. The proposed mechanism by which catecholestrogens act in carcinogenesis, involving redox cycling and the generation of free radicals, would not necessarily involve the estrogen receptor but would involve the enzymes of E2 metabolism.
|
From page 109... ...
Defining structure-activity relationships for substrate binding to homologous enzymes in different species will help to achieve generalizations. FACTORS INFLUENCING DOSE-RESPONSE ASSESSMENT A central issue in evaluating possible consequences of HAA exposure is whether the concentrations accumulating in animals and humans are sufficient to elicit changes in target cells and organs of the adult or the developing organism.
|
From page 110... ...
reaches estrogen receptors in target cells, the capacity to generate responses might not be very different among vertebrate species, although it should be pointed out that the expression of the receptor and its affinity for ligand (e.g., TCDD) binding is not necessarily predictive of responsiveness.
|
From page 111... ...
A 50% increase in free serum estradiol in male mouse fetuses induced a 40% increase in the number of developing glandular epithelial ducts emanating from the urethra (these form the glandular ducts within the prostate) ; subsequently in adulthood, the number of developing prostatic androgen receptors per cell was permanently increased by two-fold, and the prostate was enlarged by 30% (due to hyperplasia)
|
From page 112... ...
Prostate weights presented here were adjusted for significant effects of DES on body weight by analysis of covariance (ANCOVA) using the statistical analysis system (SAS)
|
From page 113... ...
, because data from the mouse and rat indicate that concentrations of free serum estradiol in fetuses are above threshold for producing responses in estrogen-responsive cells (Nonneman et al.1992; Montano et al.1995; vom Saal et al.
|
From page 114... ...
1997~. An example in the rat uterus is the inhibition of gland genesis and down-regulation of estrogen receptors, which are responses up to an order of magnitude more sensitive to estrogenic chemicals, such as DES, than is uterine weight gain (Branham et al.
|
From page 115... ...
1996~. One of the best-studied examples of tissue specificity of a chemical that interacts with estrogen receptors is tamoxifen, which is an agonist in the mouse uterus, a partial agonist and antagonist in the rat uterus, and an antagonist in the chicken oviduct (Welshons and Jordan 1987; McDonnell et al.
|
From page 116... ...
Once inside a target cell, a steroid presumably becomes available for binding to specific intracellular receptors. Additionally, binding of HAAs to human steroid-binding proteins can displace endogenous hormones, possibly affecting hormone delivery to target cells.
|
From page 117... ...
Dose-response assessment for HAAs presents a challenge, because HAAs might cause effects not only by acting as reactive molecules that attack biologic macromolecules but also by acting as stable molecules interacting with the body's natural signaling systems. On the basis of a few in vivo investigations conducted to date involving a small number of HAAs, data suggest that in some situations a nonmonotonic dose-response relationship can occur.
|
From page 118... ...
118 HORMONALLYACTIVE AGENTS IN THE ENVIRONMENT · In vivo test systems for HAAs should be used to assess the consequences of prenatal and postnatal exposure on developmentally critical or sensitive processes at concentrations commonly found in the environment. · Dose-response characteristics of recognized actions of various HAAs should be further investigated in in vitro and in vivo studies at concentrations commonly found in the environment.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.