Veterans and Agent Orange Update 1998 (1999) / Chapter Skim
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3 Toxicology
3 Toxicology
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From page 32... ...
This chapter focuses to a large extent on the toxicological effects of TCDD, because considerably more information is available on TCDD than on the herbicides. SUMMARY Toxicokinetics New information on the distribution of 2,4-D and the metabolism of cacodylic acid has improved understanding of how the body handles these sub 32
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From page 33... ...
However, it may affect enzymes and hormone levels, which in turn may produce adverse effects. Recent studies confirm earlier findings that most of the toxic effects of TCDD are caused by its binding to a protein called the aryl hydrocarbon receptor (AhR)
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From page 34... ...
It is known that TCDD exposure causes a broad range of immunologic effects in experimental animals. Recent studies support earlier data that TCDD decreases immunity and host resistance to pathogenic microorganisms.
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From page 35... ...
Functional reproductive alterations in female offspring are also observed after TCDD exposure, including decreased fertility rates and reduced fecundity. Studies in male rats and hamsters have shown that decreased daily sperm production is one of the most sensitive effects of exposure to TCDD in the womb and through breast milk.
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From page 36... ...
VAO AND UPDATE 1996 OVERVIEW Chapter 4 of VAO and Chapter 3 of Update 1996 review the results of animal and test-tube studies published until 1995 that investigated the toxicokinetics, mechanism of action, and disease outcomes of TCDD and herbicides. 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.
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From page 37... ...
This suggests that increases in UGT activity may be a useful biomarker for tumorigenic changes in hormone levels after TCDD exposure. However, certain noncancer end points may be more significant in assessing human health risks to TCDD than cancer end points.
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From page 38... ...
The recent discovery that the oxygen-regulated transcription factor HIF-loc and the AhR share a common heterodimerization partner Arnt (HIF-10) has fueled intensive investigation into the possible crosstalk between oxygen and dioxin signal transduction pathways.
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From page 39... ...
TCDD has been shown to inhibit hepatocyte DNA synthesis; decrease hepatic plasma membrane epidermal growth factor receptor; inhibit hepatic pyruvate carboxylase activity as a consequence of a reduction in pyruvate carboxylase mRNA levels (this effect was ten-fold greater than in congenic Ahb/b mice, suggesting that a competent AhR is required) ; and induce cytochrome P4501A1
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From page 40... ...
Studies have been conducted to determine whether in utero and lactational TCDD exposure decreases male rat accessory sex organ weights during postnatal development and whether this effect involved decreases in testicular androgen production or changes in peripheral androgen metabolism. Results suggest that in utero and
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From page 41... ...
Reports indicate that in ovo TCDD exposure of the domestic chicken, domestic pigeon, and great blue heron adversely affected the body and skeletal growth and hatchability of the domestic pigeon but had no effect on the domestic chicken or great blue heron. Studies involving human luteinizing granulose cells have shown that glucose transporting activity can be used as a sensitive biomarker to detect the very early response to TCDD in these steroid-producing cells and that the effect of TCDD on progesterone is mediated through cyclic adenosine 5'-monophosphate (cAMP)
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From page 42... ...
TCDD has been shown to significantly induce CYPlA1 mRNA levels and EROD activity in several human cancer cells. Experiments involving several strains of mice provide evidence that a functional Ah receptor is required for TCDD induction of CYPlA1 and liver tumor promotion.
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From page 43... ...
TCDD induction of CYPlA1 in rainbow trout hepatocytes does not appear to depend on protein kinase activity. TOXICITY PROFILE UPDATES This section updates the toxicity profiles of the five substances discussed in VAO and Update 1996: (1)
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From page 44... ...
(1997) concluded that to a small extent,2,4D increases mRNA levels of mar genes in mouse liver.
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From page 45... ...
, 1.0, 3.75, or 7.5 mg/kg daily for 13 weeks. The dogs exhibited reductions in body weight gain and food consumption, and minor increases in blood urea nitrogen, creatinine, and alanine aminotransferase as a function of chemical treatment.
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From page 46... ...
in the drinking water for 26 days at concentrations ranging from 0 to 0.42 mg/kg significantly reduced antibody production in response to inoculation with sheep red blood cells. Although the individual component responsible for this effect was not identified, it is important to note that these levels of exposure are only marginally higher than the levels encountered following recommended application of the herbicide.
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From page 47... ...
However, it must be emphasized that the dogs were concomittantly exposed to other pesticides in addition to 2,4-D. Toxicity Profile Update of 2,4,5-T Toxicokinetics No toxicokinetic studies were identified for the reference period.
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From page 48... ...
These alterations coupled with the ability of 2,4,5-T to induce mutations under certain conditions can influence the carcinogenic process. Toxicity Profile Update of Cacodylic Acid Toxicokinetics Hughes et al.
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From page 49... ...
DMA treatment (50, 100, 200, or 400 mg/kg) in the drinking water of male rats initiated by sequential treatment with nitrosamines (diethylnitrosamine [100 mg/kg, i.p., single dose]
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From page 50... ...
in drinking water for eight weeks without prior initiation was associated with a significant increase in the 5-bromo-2'-deoxyuridine labeling index and alteration of the surfaces of urinary bladder epithelial cells. These results suggest that the potential of DMA to promote rat urinary bladder carcinogenesis may be related to its ability to stimulate cell proliferation in the urinary bladder epithelium.
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From page 51... ...
For a given body burden, adipose tissue concentrations vary in inverse proportion to the mass of adipose tissues, an observation that is relevant to humans. Aozasa et al.
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From page 52... ...
This interpretation was based on the change in slope observed from low- to high-dose subsets for thymic atrophy, immune suppression, BP hydroxylase activity, and EROD activity. These investigators suggest that the power law function can provide a more accurate and biologically relevant assessment of risk and that noncancer end points may be more significant than cancer end points in assessing human health risks from TCDD.
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From page 53... ...
transforms the receptor to a form that exhibits increased DNA binding affinity leading to translocation to the nucleus where it dimerizes with a partner protein, Arnt. The AhR-Arnt complex binds to specific sequences in the regulatory region of target genes called aryl hydrocarbon-responsive elements (AhREs)
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From page 54... ...
The deduced proteins, termed rtARNTa and rtARNTb, are identical over the first 533 amino acids and contain a bHLH domain that is 100 percent identical to human Arnt. Both the AhR and Arnt have been shown to interact with a large number of proteins to influence receptor function.
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From page 55... ...
The minimal ligand binding domain maintains the quantitative and qualitative
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From page 56... ...
The C-terminal 34 amino acids of Arnt harbor a TAD that functions independently of other sequences in the AhR complex (Corton et al., 1996~. The strength of the Arnt TAD is cell-type specific since Arnt and herpes simplex virus VP16 TAD were equally strong in COS-1 cells, but the Arnt TAD had weak activity in an Arnt-deficient mouse hepatoma cell line and was not needed for restoration of CYPlA1 activation.
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From page 57... ...
(1996) transfected chimeric deletion constructs containing the AhR 5'-flanking region and the firefly luciferase reporter gene into five established mouse cell lines: Hepa lclc7 (derived from hepatoma)
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From page 58... ...
DNA Binding and Transcriptional Interference As described previously, modulation of gene expression by TCDD is dependent on its ability to bind DNA to influence transcriptional events. Recent studies have focused on characterizing the nature of TCDD-induced ligand binding (e.g., transactivation domains)
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From page 59... ...
investigated ligand-dependent differences in molecular properties of the transformed cytosolic and nuclear AhR. For several different AhR ligands including TCDD, TCDF, 1,2,7,8-TCDF, and oc-naphthoflavone, the pattern of proteolytic protein-DNA products using transformed cytosolic or nuclear AhR complexes was comparable.
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From page 60... ...
Thus, the PAS domains of the dioxin receptor and Arnt are novel dimerizing regions critical in the formation of a functional AhR-Arnt complex, whereas the PAS domain in Per is a potential negative regulator of bHLH-PAS function. Evidence was also presented that hsp90 may modulate dioxin receptor function by directing correct folding of the ligand binding domain, interference with Arnt heterodimerization, and folding of a DNA binding conformation of the bHLH domain.
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From page 61... ...
Their results suggested that TCDD induces expression of the immediate early-response genes fos and jun by activation of three separate signal transduction pathways, at least one of which does not require a functional AhR complex. The serum response elements (SRE)
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From page 62... ...
Enan and Matsamura (1996) described the ability of TCDD to increase protein-tyrosine kinase activity in the cytosol of male guinea pig adipose tissue, an effect believed to be AhR dependent.
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From page 63... ...
TCDD elevated insulin receptor mRNA levels and inhibited several other insulin-induced responses including c-fos protooncogene expression, phosphorylation of the insulin receptor, and a 185 kDa protein in MCF-7 cells. Redox Signaling The discovery that the oxygen-regulated transcription factor HIF-loc and the AhR share a common heterodimerization partner Arnt (HIF-10)
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From page 64... ...
These findings have implications for risk assessment in that TCDD itself may induce alterations in the redox status of cells. Consistent with these observations, activation of HIF-loc function in vivo or overexpression of HIF-loc inhibited ligand-dependent induction of DNA binding activity and AhR function on minimal reporter gene constructs.
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From page 65... ...
Thus, TCDD regulates the DNA binding activity of AP-1 and c-Myc by modulating their phosphorylation status through alterations in protein kinase and phosphatase activities. Incubation of a nuclear-free subcellular homogenate of guinea pig adipose tissue with TCDD results in a significant elevation of protein kinase activity within 1-10 minutes (Enan and Matsamura, 1995b)
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From page 66... ...
Finally, the association of c-Src protein kinase with AhR was described earlier (Enan and Matsamura, 1996~. Several earlier studies suggested that AhR phosphorylation may be critical in activation of the AhR to a DNA binding state.
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From page 67... ...
Inhibition of PKC activity blocked the transcriptional activation and transactivation of the CYPlA1 gene, indicating a role for PKC in the AhR-mediated transcriptional activation process. However, DNA binding activities of the in vitro activated and the induced nuclear AhR were not affected when CYPlA1 transcription was inhibited, indicating that the action of PKC is a nuclear event that works in concert with or precedes AhR binding to the gene.
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From page 68... ...
(1996b) have shown that treatment of MCF-7 human breast cancer cells with TCDD decreases prolactin receptor (PRLR)
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From page 69... ...
Both compounds competitively bind to the AhR with low affinity. In Ahresponsive T47D human breast cancer cells, I3C and DIM do not induce EROD activity or CYPlA1 mRNA levels.
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From page 70... ...
Exposure to ADSS induced transformation and DNA binding of the AhR complex. Collectively, these results indicate a role for the AhR in mediating the induction of CYPlA1 by ADSS and suggest that environmentally relevant levels of ADSS contain AhR ligands at sufficient concentrations to activate gene expression in an AhR-dependent manner.
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From page 71... ...
Female rats were dosed orally with either 5.3, 12, 18, and 60 ,ug TCDD/kg and sacrificed four days after dosing or 27, 40, and 60 ,ug TCDD/kg and sacrificed 90 days after dosing. Four days after dosing, EROD activity was fully induced at all doses studied, hepatic PEPCK and y-glutamyl transpeptidase activities were reduced dose dependently, and hepatic tryptophan 2,3-dioxygenase (TdO)
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From page 72... ...
of TCDD administered orally by gastric intubation on serum hormone levels in female rats (22 days old)
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From page 73... ...
These results suggest that TCDD dose dependently induces a brief release of gonadotropins in immature female rats. This effect is at least partially due to an effect of TCDD on the pituitary.
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From page 74... ...
EROD rates in intact cells maximally induced by BP, TCB, or TCDD ranged from 15 to 30 pmol/mg per minute of whole-cell protein. Methoxyresorufin O-demethylase activity induced by TCDD was 2 pmol/ mg per minute (i.e., <10 percent of EROD activity)
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From page 75... ...
In porcine cells exposed to 0.1 nM TCDD and 10 ,uM cortisol, the level of CYPlA1 protein and the degree of EROD activity induction were two- to threefold higher than with 0.1 nM TCDD alone. A similar enhancement of EROD induction was obtained when 0.1 or 1 nM TCDD was added together with 0.1,1, or 10 M dexamethasone in the media.
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From page 76... ...
It seems likely that inappropriate expression of PGHS-2 may contribute to the toxic effects of TCDD and other halogenated aromatic hydrocarbons (HAHs)
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From page 77... ...
Hushka and Greenlee (1995) have shown that TCDD caused a dose-dependent inhibition of DNA synthesis in primary hepatocytes isolated from either male or female Sprague-Dawley rats in the presence or absence of known hepatocyte mitogens (epidermal growth factor [EGF]
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From page 78... ...
mRNA levels in Ahb/b mice. This response was tenfold greater than in congenic Ahb/b mice, suggesting that previously reported reduction in PC activity by TCDD treatment of mice is a consequence of a reduction in PC mRNA levels and that the effect requires a competent AhR.
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From page 79... ...
In agreement with DNA synthesis data, the level of c-dun was increased or decreased in nuclear extracts. Furthermore, DNA binding of Jun/Fos proteins, including c-dun and Fra-l, was decreased under conditions of mitoinhibition, while the level of Fra-1 in nuclear extracts was increased.
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From page 80... ...
In adipose tissue, a slight recovery was observed by 30 days, but in the brains of treated animals, glucose transport was significantly decreased even at the latest time. A comparison of dose-response relationships for several tissues between C57BL/6 (TCDD responsive)
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From page 81... ...
In contrast to liver, TCDD treatment increased PEPCK activity in kidney and brown adipose tissue, but only at the two highest doses administered (30 and 60 ,ug/kg)
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From page 82... ...
This interesting enzymatic constellation suggests that the reduction in gluconeogenesis due to decreased PEPCK activity in liver is partially counterbalanced by increased gluconeogenesis in kidney as a result of induction of PEPCK in this organ. Induction of PEPCK in brown adipose tissue (BAT)
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From page 83... ...
TCDD induced the DNA binding of AP-1 in adipose tissues of male guinea pigs, but in female tissues, TCDD reduced the DNA binding of AP- 1. Endocrine Effects Sewall et al.
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From page 84... ...
A relationship between glucose transporting activity and progesterone production in human LGCs treated with TCDD is suggested by the finding that cytochalasin B down-regulated glucose transporting activity and progesterone production, insulin plus D-glucose down-regulated glucose uptake and amplified the negative effect of TCDD on progesterone production, and forskolin abolished the negative effect of TCDD on glucose transporting activity and on progesterone production. From these data it was concluded that glucose transporting activity can be used as a sensitive biomarker to detect the very early response to TCDD in human steroid-producing cells and that the effect of TCDD on steroid production is mediated through the cAMP-dependent protein kinase.
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From page 85... ...
Immunotoxicity TCDD and structurally related halogenated aromatic hydrocarbons have a broad range of immunologic effects in experimental animals, including effects on host resistance and innate, cell-mediated, and humoral immune responses (Kerkvliet, 1995~. As discussed in VAO and Update 1996, thymic atrophy is the most consistent biological effect found in laboratory animals treated with TCDD and is believed to be mediated primarily through the T-cell arm of the immune system.
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From page 86... ...
There was a dose-dependent decrease in the relative size of the cortex of both normal rat thymus and grafted human thymus; the decrease was significant in the highest-dose group. Only limited data were obtained from grafted rat thymus because of a cutaneous graft-versus-host reaction, but they were consistent with those in normal rat and grafted human thymus.
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From page 87... ...
The mRNA levels of TNF were also significantly elevated, beginning at 30,ug/ kg TCDD. These results suggest that at low doses of TCDD, increased levels of IL- 1 ~ may account for immune function stimulation, whereas at high doses, greatly elevated TNF and IL-1p levels might exacerbate or mediate acute toxicity such as immune suppression and related biochemical effects.
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From page 88... ...
. In an in vivo study, administration of 15 ,ug/kg TCDD to mice followed by an injection of anti-CD3 two days later significantly reduced plasma levels of IFN and elevated plasma levels of IL-6 and GM-CSF, suggesting that increased IL-6 and GM-CSF contributed to the toxic effects of TCDD.
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From page 89... ...
Thymic atrophy is a prominent effect of TCDD exposure. In the presence of TCDD, the distribution of CD4/CD8 thymocyte subsets is strongly skewed toward CD4-CD8+ single positives.
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From page 90... ...
searched the published data on genes important in B-cell function for DNA sequences that have homology to the consensus AhR binding site. This approach identified a subset of DNA binding sites for the transcription factor B-cell lineage-specific activator protein (BSAP)
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From page 91... ...
The inability to detect binding of the T-cell nuclear AhR complex to a consensus response element, combined with difficulties of reproducing in vivo immunotoxic effects of TCDD in vitro suggests that T cells may lack one or more factors required for AhR binding to a DRE or may contain a suppressor factor that inhibits AhR binding to DNA. Based on these data, it was suggested that TCDD affects T-cell function via an indirect mechanism.
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From page 92... ...
TCDD suppressed murine B-cell IgM secretion induced by anti-IgM, but did not affect IgM secretion stimulated by activated T cells through the CD40 pathway. Because mobilization of calcium has been shown to be an integral event in the stimulation of proliferation via the antigen receptor in B cells, the effect of TCDD exposure on B-cell intracellular calcium concentration and mobilization was examined.
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From page 93... ...
(1995) recently completed studies to determine whether in utero and lactational TCDD exposure decreases male rat accessory sex organ weights during postnatal development and whether this effect involves decreases in testicular androgen production or changes in peripheral androgen metabolism.
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From page 94... ...
and cauda epididymal sperm number are some of the most sensitive effects of in utero and lactational TCDD exposure. To determine if TCDD exposure increases the rate of sperm transit through the excurrent duct system, thereby decreasing the number of sperm in the system at any given time, pregnant Holtzman rats were administered a single dose of TCDD (1.0 fg/kg, p.o.)
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From page 95... ...
These data suggest that administration of a single dose of 1 fg TCDD/kg on GD 15 results in malformations of the external genitalia in female LE and Holtzman rats. Although treatment on GD 15 is generally more toxic to the offspring than treatment on GD 8 with respect to growth, viability, male reproductive effects, and malformations of the external genitalia in female progeny, treatment on GD 8 is more effective in inducing functional reproductive alterations in female progeny.
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From page 96... ...
In heron, EROD activity was induced two- to threefold above control birds; however, no effect was observed on plasma thyroid hormone levels or body growth. Thus, in ovo TCDD exposure adversely affected the body and
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From page 97... ...
In herons, TCDD exposure had no effect on hepatic ER levels or plasma estradiol and testosterone concentrations at either time. Based on these results it was concluded that in chicken, pigeon, and great blue heron hatchlings exposed early in incubation to low doses of TCDD, hepatic ER levels and plasma estradiol concentrations are not altered.
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From page 98... ...
In addition, cardiac expression of an AhR-Arnt target CYPlA1 was restricted to myocardium coexpressing AhR and Arnt. Thus, the spatial and temporal expression of AhR and Arnt suggests that the developing myocardium and cardiac septa are potential targets of TCDD-induced teratogenicity, and such targets are also consistent with cardiac hypertrophy and septal defects observed after TCDD exposure.
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From page 99... ...
Estrogen receptor mRNA increased in the hypothalamus, uterus, and ovary and decreased in the pituitary. The results of DNA binding assays paralleled the mRNA profile of the uterus, whereas DNA binding activity was decreased in the hypothalamus and unchanged in ovarian protein extracts.
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From page 100... ...
on induction of CYPlA1 mRNA levels and EROD activity. With the exception of the MDA-MB-231 breast cancer cell line, TCDD significantly induced CYPlA1 mRNA levels and EROD activity in the remaining six cell lines.
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From page 101... ...
Both cell lines have been characterized with respect to their AhR concentrations and induce CYPlA1 in response to exposure to xenobiotics such as TCDD. Using an AhR antagonist, ocnaphthoflavone, and a protein kinase C inhibitor, staurosporine (ST)
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From page 102... ...
Each cytochrome P450 exhibits a surprisingly similar pattern of hormonal regulation even though expressed in different cell types. In MCF-7 human breast cancer cells, E2 induction of cat D gene expression is associated with formation of an ER-Spl complex within the promoter region (-199/-165)
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From page 103... ...
Although there was a significant sevenfold increase over two days in the excretion rate of oxo8Gua into the growth medium of TCDD-treated Hepa lclc7 cells compared to controls, no significant increase was detected in the steady-state level of oxo8dG in the DNA presumably due to efficient DNA repair. Thus, the induction of CYPlA1 appears to result in a leak of oxygen radicals and consequent oxidative DNA damage that could lead to mutation and cancer.
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From page 104... ...
Transiently expressed AhR has a high basal activity on promoters containing AhR binding sites when transfected into receptor-deficient variant cells compared to wild-type cells. Single- and double-hybrid analysis dissociates AhR ligand responsiveness, transactivation, and heterodimerization with Arnt from receptor binding to a xenobiotic response element (XRE)
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From page 105... ...
Estimating Potential Health Risk and Factors Influencing Toxicity Several approaches have been used to estimate the potential health risks associated with TCDD exposures. These include the use of TEFs, quantitative structure-activity relationships, H4IIE-luc cells, toxicity equivalent concentrations (TECs)
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From page 106... ...
For instance, the total toxicity of a mixture of halogenated aromatic hydrocarbons is not necessarily the sum of the toxicities of individual congeners because individual congeners can compete for the same receptor; therefore, nonadditive behavior may occur. Furthermore, TEFs have not been tested for all effects of dioxin and dioxin-like chemicals, nor have all responses for all chemicals of concern been examined.
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From page 107... ...
(1996) developed a method for rapid screening of environmental samples containing Ahactive polyhalogenated aromatic hydrocarbons (PHAHs)
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From page 108... ...
Results of this investigation indicate that chloracne and induction of CYPlAl, effects clearly associated with dioxin, occur at similar body burdens in humans and animals. Induction of cancer in animals occurs at body burdens of 944-137,000 ng TCDD/kg body weight, whereas noncancer effects in animals occur at body burdens of 10-12,500 ng/kg.
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From page 109... ...
This has not, however, simplified the risk assessment process because the toxicologic profile of TCDD is rather complex. In general, there is consensus that most of the toxic effects of TCDD involve interaction with the aryl hydrocarbon receptor, a protein that binds TCDD and other aromatic hydrocarbons with high affinity.
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From page 110... ...
Expression of aryl hydrocarbon receptor nuclear translocator in the C57BL6N mouse embryo. Developmental Dynamics 204(2)
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From page 111... ...
Demonstration of a unique tissue-specific pattern of hormonal and aryl hydrocarbon receptor-linked regulation. Journal of Biological Chemistry 270(19)
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From page 112... ...
1996. Protein kinase C modulates regulation of the CYPlA1 gene by the arylhydrocarbon receptor.
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From page 113... ...
of the DNA binding activity of transcriptional factors via nuclear protein phosphorylation in guinea pig adipose tissue. Biochemical Pharmacology 50:1199-1206.
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From page 114... ...
1995. Identification of functional domains of the aryl hydrocarbon receptor.
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From page 115... ...
1996. Uroporphyrin accumulation associated with cytochrome P4501A induction in fish hepatoma cells exposed to aryl hydrocarbon receptor agonists, including 2,3,7,8-tetrachlorodibenzo-p-dioxin and planar chlorobiphenyls.
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From page 116... ...
1995. Aromatic hydrocarbon receptor in cultured fetal cells from C57BL/6J and DBA/2J mice: similarity in molecular mass to receptors in adult livers.
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From page 117... ...
1996. Dioxin-induced CYPlA1 transcription in viva: the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure.
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From page 118... ...
1995. The Ah receptor recognizes DNA binding sites for the B cell transcription factor, BSAP: a possible mechanism for dioxin-mediated alteration of CDl9 gene expression in human B lymphocytes.
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From page 119... ...
1995. Regulation of cytochrome P4501A1 gene expression in vascular smooth muscle cells through aryl hydrocarbon receptor-mediated signal transduction requires a protein synthesis inhibitor.
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From page 120... ...
1996. Trans-activation by the human aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator proteins: direct interactions with basal transcription factors.
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From page 121... ...
1995. Induction of cytochrome P4501A1 by aryl hydrocarbon receptor agonists in porcine aorta endothelial cells in culture and cytochrome P4501A1 activity in intact cells.
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From page 122... ...
1996. Retinoic acid affects the expression rate of the differentiation-related genes aryl hydrocarbon receptor, ARNT and keratin 4 in proliferative keratinocytes only.
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From page 123... ...
1995. Functional analysis of aryl hydrocarbon receptor nuclear translocator interactions with aryl hydrocarbon receptor in the yeast two-hybrid system.
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