Veterans and Agent Orange Update 2000 (2001) / Chapter Skim
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3 Toxicology
3 Toxicology
Pages 22-102
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From page 22... ...
, picloram, and cacodylic acid. In addition, the toxicologic properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin)
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From page 23... ...
According to these earlier reviews, TCDD elicits a diverse spectrum of biological sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. The scientific consensus is that TCDD is not directly genotoxic and that its ability to influence the carcinogenic process is mediated via epigenetic events such as effects on enzyme induction, cell proliferation, apoptosis, and intracellular communication.
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From page 24... ...
2,4,5-T also affected Neu tyrosine kinase, a tyrosine kinase receptor that has been shown in other experiments to be correlated with an increased incidence of breast cancer. The relevance of the effects of 2,4,5-T on that enzyme to the toxic effects of 2,4,5-T is unknown.
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From page 25... ...
Additional research demonstrates that the biochemical and biological outcomes of TCDD exposure can be modulated by numerous other proteins with which the AhR interacts. It is plausible, for example, that the AhR could divert other proteins and transcription factors from other signaling pathways; the disruption of these other pathways could have serious consequences for a number of cell and tissue processes.
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From page 26... ...
Recent data also suggest that promotion of liver tumors by TCDD in female rats is dependent on continuous exposure to TCDD. Relevance to Human Health As indicated above, exposure to 2,3,7,8-TCDD has been associated with both cancer and noncancer end points in animals, and most TCDD effects are mediated through the AhR.
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From page 27... ...
No single mechanism has been established as underlying the toxic effects of TCDD, and with the many different effects seen, more than a single mechanism might exist. It is hoped that as the cellular mechanisms of these compounds are discovered, subsequent VAO updates will have better information on which to base conclusions and to aid in determining the relevance of experimental data to effects in humans.
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From page 28... ...
2,4-D has previously been shown to have low oncogenic potential, with genotoxic effects seen only at high concentrations. Recent evidence is consistent with these earlier data.
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From page 29... ...
Studies published since Update 1998 are consistent with the hypothesis that TCDD produces its biological and toxic effects by binding to the AhR. For example, recent data indicate that TCDD has only minimal teratogenicity, if any, in AhR knockout mice compared to wild-type mice.
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From page 30... ...
Decreased motor activity, muscle weakness, motor incoordination, decreased weight gain, and serum alterations were seen only at doses greater than 100 mg/kg. Reversible and permanent behavioral alterations have also been seen in rats following treatment with high doses of 2,4-D from gestational day 16 to postnatal day 23.
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From page 31... ...
Increased parasitic larval burdens occurred in rats following TCDD exposure; there was some indication that age increased the sensitivity of humoral immunity to TCDD exposure. TCDD has been shown to decrease delayed-type hypersensitivity responses, decrease the total percentage of CD4+ cells and the percentage of the CD4+ cells cycling following repeated exposure, and stimulate the production of interleukin-2 (IL-2)
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From page 32... ...
In utero and lactational exposure of rats to TCDD decreased prostate weight without inhibiting testicular androgen production or decreasing serum androgen concentrations. Additional studies showed that the prostatic epithelial budding process was impaired, suggesting that in utero and lactational TCDD exposure interferes with prostate development by decreasing early epithelial growth, delaying cell differentiation, and producing alterations in epithelial and stromal cell histological arrangement and the spatial distribution of androgen receptor expression.
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disease outcomes, and if applicable, (4) estimating potential health risks and factors influencing toxicity.
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The results indicate that the toxic effects of Tordon 75D on SMPs and intact rat liver mitochondria were caused mainly, if not solely, by the proprietary surfactant. Rosso and coworkers (2000)
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IC50 values of 2,4-D in these cell lines ranged from 0.87 to 1.3 mg/ml. Evaluation of data for the other chemicals suggests that the experimental IC50 values are as accurate predictors of human toxicity as equivalent blood concentrations derived from rodent LD50 studies.
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The no-observable-adverse-effect level (NOAEL) for maternal toxicity in rats was 31.25 mg/kg/day based on decreased body weight gain.
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A NOAEL of 2.48 mg/kg/day for male rats and 3.23 mg/kg/day for female rats was observed based on decreased body weight gain. Minor histopathological lesions were thought to be due to decreased body weight gain.
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From page 38... ...
Those data suggest that 2,4,5T has a relatively weak potency to produce myelotoxicity. Toxicity Profile Update of Cacodylic Acid Cacodylic acid (dimethylarsinic acid, DMA; Chemical Abstracts Service [CAS]
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and dimethylarsinic acid (DMA) is a pathway of inorganic biotransformation.
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From page 40... ...
Using scanning electron microscopy to evaluate urothelial toxicity and hyperplasia after 10 weeks of exposure, it was determined that the urothelial effects of DMA were reversible, that the toxicity is probably not due to urinary solids, and that the toxicity and regeneration are produced in a dose-responsive manner in female rats. In a similar study (M.
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From page 41... ...
Toxicity Profile Update of TCDD Toxicokinetics The distribution of planar halogenated aromatic hydrocarbons, including specific congeners of the polychlorinated dibenzo-p-dioxins (PCDDs) , polychlorinated dibenzofurans (PCDFs)
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From page 42... ...
The retention of TCDD is decreased by the presence of other PHAHs. These researchers showed that liver lipid content was positively correlated with retention of non-AhR agonists but that no such correlation was observed with TCDD or TCDF; the authors suggested that the lack of correlation results from CYP1A2 binding of the latter compounds.
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From page 43... ...
TCDD levels in blood were correlated with levels in adipose tissue, kidney, spleen, liver, and brain. However, there was no correlation between blood levels of TCDD and the levels in muscle or lung.
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From page 44... ...
A dose of 1.15,ug/kg on gestation day 8 produced fetal body burdens of 18.1 to 39.6 ng/kg, depending on the time of gestation. The authors note that the doses used were in the range of body burdens of 2,3,7,8-TCDD toxicity equivalents (TEQs)
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PCDDs and PCDFs formed in vitro from peroxidase-catalyzed reactions with chlorophenol substrates (Wittsiepe et al., 1999~. Such results raise questions about interpretations regarding exposure levels or body burdens based on analysis of excreted residues.
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From page 46... ...
TCDD levels in serum ranged from 7.6 pg/g serum lipid in nonexposed workers to 105 pg/g in workers exposed to the accident who had chloracne. The back-extrapolation employed a one-compartment first-order model, for which the authors varied assumptions concerning half-life, using three values that have been derived largely from studies of Vietnam veterans: 5.8, 7.1, and 11.3 years.
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From page 47... ...
Additional research has shown that the biochemical and biological outcomes of TCDD exposure can be modulated by numerous other proteins with which the AhR interacts. Thus, it is now considered possible that TCDD could modulate gene expression by pathways that do not involve the interaction of the AhR with either ARNT or DREs.
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(1998) observed a good correlation between the steady-state level of AhR expression and the relative inducibility of CYPlA1 in eight different rat strains.
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Different AhR agonists displayed additive responses within this system. The author indicated that this may provide a useful model for further study and characterization of AhR agonists and AhR-dependent signal transduction pathways.
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, were identified. TCDD exposure elicits developmental alterations in many species and induces cleft palate in the mouse embryo.
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(1999) examined the effects of stage of development and TCDD treatment on AhR protein, ARNT protein, and mRNA concentrations in rat prostate.
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The minimum AhR nuclear localization signal was contained in residues 13-39 of the human AhR, while the minimal nuclear export signal was contained in residues 55-75. Several investigations utilizing whole animals and cells in culture demonstrated that TCDD treatment elicits a sustained depletion of AhR protein, without an effect on AhR mRNA, in a variety of tissues (Giannone et al.,1998; Pollenz et al., 1998; Roman et al., 1998a)
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DNA binding and transactivation domains have been identified in both the AhR and ARNT. However, it is clear that the ability of this activated complex to induce particular genes
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The presence of this factor may account for the selective expression of CYPlA1 over CYPlB1 in some cell types with and without TCDD exposure. Studies by Mimura et al.
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found that CYPlAl-deficient mouse hepatoma c37 cells possess transcriptionally active AhR-ARNT complexes in the absence of exogenous ligands. A similar finding was observed following treatment of Hepa-1 cells with an inhibitor of CYPlA1 activity.
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These data indicate that TCDD can initiate altered gene expression in these tissues, thereby identifying potential targets of toxicity. Biological Consequences of Activation Many toxic effects of TCDD have been described in experimental animals and exposed human populations.
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Liver lesions have been reported in several animal species following exposure to TCDD, and this chemical is a potent tumor promoter in the liver of male and female mice, as well as female rats. Two recent studies evaluated the relative contributions of different cell types to the hepatic lesions observed in rats.
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The greatest reduction achieved was 44 percent in female rats. No effect on male rats was observed.
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(1999) investigated the dose-dependent expression of CYPlAl, CYP1A2, and CYPlB1 in the livers of female rats exposed for 30 weeks to doses of TCDD up to 125 ng/kg/day.
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(1998) investigated the time course and reversibility of cell proliferation in control and diethylnitrosamineinitiated female rats exposed biweekly to an average daily dose of 125 ng TCDD/ kg/day for up to 60 weeks.
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(1998) examined whether resting or activated T cells are more susceptible to TCDD exposure.
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Finally, another study found that TCDD concentrations of 1-40 nM induced apoptosis in two cultured human leukemic lymphoblastic T cell lines. However, two other AhR ligands, 2,3,7,8-tetrachlorodibenzofuran and p-naphthoflavone failed to elicit apoptosis even at concentrations up to 20 Ad.
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From page 63... ...
A single oral dose of 2,ug TCDD/kg to pregnant hamsters at gd 11.5 altered reproductive tissue and function in female offspring (Wolf et al., 1999~. Body weights were reduced, vaginal opening was delayed, and vaginal estrous cycles were altered.
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From page 64... ...
and AhR presence on AhR signal transduction pathways in the developing mouse mammary gland. In untreated 6to 8-week-old Ahr null-allele littermates, there were reductions of terminal end buds and increased numbers of blunt-ended terminal ducts.
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From page 65... ...
Because Kipl appears to act as a tumor suppressor gene, at present it seems unlikely that the effects of TCDD on this gene could underlie some of TCDD's carcinogenicity and tumor-promoting activity. It has been shown that TCDD induces a Go cell cycle arrest in rat 5L hepatoma cells via the AhR (Ma and Whitlock, 1996~.
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From page 66... ...
There was also a concentration-dependent increase in expression of IL-01 and PAI-2 mRNA in immortalized human endometrial stromal cells following TCDD treatment (Yang, 1999~. Expression of PAI-2 mRNA appeared to be altered by TCDD at the posttranscriptional level.
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From page 67... ...
is one of the genes shown to be altered by TCDD exposure. This protein is a serine protease that is involved in matrix turnover and growth of tumor cells.
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From page 68... ...
Several previous investigations suggest that reactive oxygen species (ROS) might be generated by the increased presence of several of the cytochrome P450 isozymes known to be induced by TCDD and related halogenated aromatic hydrocarbons.
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A single TCDD treatment of 1 ,ug/kg resulted in an increase in nuclear protein tyrosine kinase within 1 day after treatment. The activity had returned to near control levels by day 40.
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Exposure to 1 nM TCDD decreased cytosolic c-src and increased c-src in the plasma membrane. EGFR tyrosine phosphorylation was also enhanced by TCDD treatment.
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From page 71... ...
TCDD treatment inhibited ovulation; this inhibition was potentiated by estradiol treatment in hypophysectomized but not intact animals. Only hypophysectomized rats exposed to both TCDD and estradiol showed weight loss.
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(1998d) investigated the effect of TCDD treatment on the ability of estradiol to alter kinase activities in adipose tissues of immature and mature female rats.
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(1999b) demonstrated an interaction between the AhR and testosterone signal transduction pathways.
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From page 74... ...
Significant Interactions Research has identified other groups of chemicals that may either interact directly with the AhR or affect AhR function indirectly. When exposure to such chemicals and TCDD occurs, the toxicological consequences of TCDD exposure can be modified.
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Treatment of guinea pigs with a single dose of 1,ug TCDDlkg produced decreased body weight gain and decreased testicular weight (there was no effect on testes weight, however, when the data were expressed as percentage of body weight)
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Mortality occurred in the 1, 10, and 100 ppb groups, and these mink displayed the classic symptoms of the wasting syndrome (i.e., extreme loss of body weight, decreased food consumption with an increase in consumption prior to death, and bloody stool)
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levels were unaffected by TCDD when female rats were killed 4 days after dosing. However, at 90 days, postdosing, serum T3 and T4 were both dose dependently elevated (Fan and Rozman, 1995~.
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Many immunotoxicological studies involving TCDD have been conducted over the past two decades in mice. It has been demonstrated by many investigators that the consequences of TCDD exposure include suppression of the antibody plaque-forming cell (PFC)
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From page 79... ...
The authors concluded that agerelated immunosuppression did not exacerbate TCDD-induced suppression of Tcell-mediated expulsion of adult parasites and, in fact, provided some degree of protection. However, a lower dose of TCDD in aged rats suppressed humoral and cellular responses that limited the burden of encysted larvae, suggesting that age increases the sensitivity of humoral immunity to TCDD exposure.
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From page 80... ...
Although reduced body weight gain and histopathology confirmed that a single 25 ,ug/kg oral dose of TCDD caused morbidity but not mortality in L-E rats, the effect on the immune system was one of stimulation or no effect in an activated (TCDD + superantigen) versus nonactivated (TCDD)
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From page 81... ...
Since "endocrine-related" effects occurred only at the highest dose of TCDD in the female, it was concluded that male offspring are more susceptible to TCDD than female progeny when exposure occurs throughout pregnancy and lactation. Additional studies have shown that when pregnant female rats were administered a single oral dose of TCDD (10 ,ug/kg)
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From page 82... ...
showed that the prostatic epithelial budding process was impaired, suggesting that in utero and lactational TCDD exposure interferes with prostate development by decreasing early epithelial growth, delaying cytodifferentiation, and altering epithelial and stromal cell histological arrangement and the spatial distribution of androgen receptor expression. Pregnant L-E rats were Savaged on gd 15 with 1.0 ,ug/kg TCDD, and their male offspring were necropsied at intervals up to 120 days postnatally to observe the effects of TCDD on seminal vesicles (Hamm et al., 2000~.
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From page 83... ...
The incidence of hepatocellular adenomas and carcinomas, however, was significantly decreased in rats treated with 1.75 ,ug/kg TCDD for 30 weeks followed by no TCDD treatment for an additional 30 weeks, compared to the TCDD continuously treated and vehicle control groups. Although there may be several other explanations, such as differences in total dosage delivered, the authors interpreted these data to suggest the possibility that the promotion of liver tumors by TCDD in female rats is dependent upon continuous exposure to TCDD.
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From page 84... ...
Extrapolation to a meaningful dose may add considerable uncertainty to calculation of the 2,3,7,8-TCDD toxicity equivalent (TEQ) to which an individual may have been exposed.
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From page 85... ...
In general, there is consensus that most of the toxic effects of TCDD involve interaction with the AhR, a protein that binds TCDD and other aromatic hydrocarbons with high affinity. The development of AhR knockout mice has helped to establish a definitive association between the AhR and TCDD-mediated toxicity.
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2000a. Flavones and flavonols at dietary levels inhibit a transformation of aryl hydrocarbon receptor induced by dioxin.
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From page 87... ...
2000. Estrous cycle-dependent changes in the expression of aromatic hydrocarbon receptor (AHR)
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From page 88... ...
pyrene in human lung adenocarcinoma cell lines: the absence of aryl hydrocarbon receptor activation. Life Sciences 65(13)
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From page 89... ...
1998. Influence of aromatic hydrocarbon receptormediated events on the genotoxicity of cigarette smoke condensate.
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From page 90... ...
through disruption of the protein phosphorylation pathway in adipose tissue from immature and mature female rats. Biochemical Pharmacology 55(7)
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From page 91... ...
to the aryl hydrocarbon receptor but inhibit nuclear uptake and transformation. Molecular Pharmacology 55(4)
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From page 92... ...
1998. Strain differences in cytochrome P450 lA1 gene expression caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver: role of the aryl hydrocarbon receptor and its nuclear translocator.
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From page 93... ...
and the aryl hydrocarbon receptor nuclear translocator (ARNT) in fetal, benign hyperplastic, and malignant prostate.
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From page 94... ...
1998. Expression of functional aromatic hydrocarbon receptor and aromatic hydrocarbon nuclear translocator proteins in murine bone marrow stromal cells.
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1998. Protein kinase C activity is required for aryl hydrocarbon receptor pathway-mediated signal transduction.
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1998. Point mutation in intron sequence causes altered carboxyl-terminal structure in the aryl hydrocarbon receptor of the most 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant rat strain.
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A function independent of aryl hydrocarbon receptor nuclear translocator. Journal of Biological Chemistry 274(4)
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2000. The aryl hydrocarbon receptor, a basic helix-loop-helix transcription factor of the PAS gene family, is required for normal ovarian germ cell dynamics in the mouse.
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1997. Aryl hydrocarbon receptor-dependent induction of Cyplal by bilirubin in mouse hepatoma Hepa lclc7 cells.
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l999b. Expression of the arylhydrocarbon receptor and the arylhydrocarbon receptor nuclear translocator during early gestation in the rabbit uterus.
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From page 101... ...
Toxicology and Applied Pharmacology 147:151-168. Wang X, Santostefano MJ, DeVito MJ, Birnbaum LS.
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1998. The involvement of aryl hydrocarbon receptor in the activation of transforming growth factor-beta and apoptosis.
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