Veterans and Agent Orange Update 2002 (2003) / Chapter Skim
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3. Toxicology
3. Toxicology
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From page 30... ...
on behavior and neurochemical alterations in the rat brain. 2,4-D induced a regionally specific neurotoxicity in the basal ganglia, but the neurotoxic effects depended on the location of injection, the dose, and the length of time since the injection.
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From page 31... ...
They conclude that there is a lack of reproductive and developmental toxicity by any route of administration at 2,4-D doses that do not exceed 50 mg/kg body weight, a dose that saturates renal clearance mechanisms, and that offspnng of treated pregnant animals show mild to moderate alterations in skeletal development only in the presence of overt maternal toxicity. Those conclusions are consistent with the data presented in this and previous updates.
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From page 32... ...
Those conclusions are consistent with the conclusions of the present and previous updates. TOXICITY PROFILE UPDATE OF 2,4,5-T No relevant studies on the toxicokinetics of 2,4,5-T or the disease outcomes seen in experimental animals after exposure to 2,4,5-T have been published since Update 2000.
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From page 33... ...
Dimethylarsin~c acid is resistant to hydrolysis, and is not demethylated to inorganic arsenic. Although dimethylarsinic acid is formed and an active metobolite in humans following inorganic arsenic exposure, as discussed in Chapter 2, it has not been established and cannot be inferred that the effects seen following exposure to inorganic arsenic occur following exposure to cacodylic acid.
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From page 34... ...
In a recent initiation-promotion study, however, cacodylic acid given in the Winking water at 220 ppm for 29 weeks did not act as a promoter of kidney tumors in male NCI-Black Reiter rats initiated with N-ethyI-N-hydroxyethyinitrosamine (Vijayaraghavan et al 2000~. In another study, a dose-dependent increase in the incidence of transitional-cell carcinoma occurred in the urinary bladder of male rats given cacodylic acid at 50 or 200 ppm in the drinking water for 104 weeks starting at the age of 10 weeks (\Vei et al., 1999~.
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From page 35... ...
The results of those studies suggest that exposure to herbicide formulation containing 2,4-D and picloram can cause male-mediated birth defects or other adverse reproductive outcomes. TOXICITY PROFILE UPDATE OF TCDD Toxicokinetics The distribution of TCDD and other chiorodibenzo-p-dioxin congeners has been examined extensively in animal models and to a smaller extent in humans over the last 2 decades.
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From page 36... ...
congeners in female rats and their offspring. Mixtures of nine dioxin-like compounds were given to female Long-Evans rats at various doses to determine transfer to the placenta, fetuses, and pups.
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From page 37... ...
The authors did not report on TCDD in semen, a possible route of transfer to the female partners. Earlier studies have measured TCDD in semen samples from Vietnam veterans (Schecter et al., 1996~; the findings suggest a possible mechanism of male-mediated adverse reproductive outcomes after Agent Orange or other dioxin exposure.
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From page 38... ...
Table 3-1 Estimates of TCDD Half-Life in Humans and Animals Reference Half-lifea Confidence Interval Comment Human Studies Pirkle et al., 1989 7.1 yr 5.8-9.6 yr Adult males, Ranch Hands 9-23 yr PE Michalek et al., 2002 7.5 yr Adult males, Ranch Hands 9-33 yr PE Flesch-Janys et al., 1996 7.2 yr Adult males, Boehringer cohort Needham et al., 1995 7.8 yr 7.2-9.7 yr Adults, Seveso cohort Michalek et al., 2002 6.9 yr Adult males, Seveso cohort, 3-16 yr PE 9.8 yr Adult females, Seveso cohort, 3-16 yr PE 0.34 yTb Adult males, Seveso cohort, ~3 mo PE Geusau et al., 2002 1.5 yrb Adult female, severe exposure 0-3 yr PE 2.9 yrb Adult female, severe exposure 0~3 yr PE Animal Studies Viluksela et al., 1996 20.2 days Rats, Long-Evans TurkuAB strain 28.9 daysC Rats, Long-Evans Charles River strain Weber et al., 1993 16.3 ~ 3.0 days Rats, male Sprague-Dawley Pohjanvirta et al., 1990 21.9 days Rats, male HanM~istar resistant strain 38
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From page 39... ...
Serum TCDD concentrations in the Seveso cohort were available Tom samples obtained within days of exposure, providing a measured initial dose, whereas the earliest serum measurements in the Ranch Hand population were obtained in 1982 and at 5-year intervals thereafter to 1997, or 9-33 years after initial exposure. The mean half-life in the Seveso males during the first 3 months after exposure was 0.34 year.
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From page 40... ...
Despite the substantial knowledge, however, it still is quite difficult to reconstruct initial exposure levels from blood levels taken much later. Mechanisms of Toxic Action Studies published since Update 2000 are consistent with the hypothesis that TCDD produces its biologic and toxic effects by binding to a gene regulatory protein, the ary} hydrocarbon receptor (AhR)
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From page 41... ...
adseverin p27Kipl 5-alpha reductase 2 low molecular weight prekinonogen metallothionein poly(ADP-ribose) polymerase NMDA receptor carboxylesterase IgE-dependent histamine-releasing factor glucose transporter 3 estrogen receptor malic enzyme epidermal growth factor receptor (EGFR)
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From page 42... ...
and K; dystrophin-associated glycoprotein 1; mannosidase alpha type II; VAMP 8; VAMP-associated protein; ankyTin 2, neuronal; gamma-butyrobetaine hydroxylase; epimorphin; membrane fatty acid desaturase; sulfotransferase 2B family member; N-methylpurine-DNA glycosylase; thioredoxin peroxidase; 3-hydroxybutyrate dehydrogenase; suppressor of Ty homolog; estrogen sulfotransferase; ma~lr~alian mutS homolog; endonuclease G; cytochrome c-1 Frueh et al., 2001 G protein-coupled receptor HM74; agrin precursor-like protein; enhancer of filamentation; XMP; cytochrome b5; DNA-binding protein inhibitor ID-2; aquaporin 3-like protein; mannose-binding protein C precursor; coagulation factor XI; arylacetamide deacetylase; cytochrome P450 subfamily XIX; calponin; endothelial actin-binding protein; phospholipase A2, membrane-associated precursor; keratin 17; apolipoprotein C-1 precursor; lectin galactdoside-binding soluble 3 (galectin 3~; phospholipase D; ATP synthase lipid-binding protein P1 precursor; glutaminyl-tRNA synthetase; hybrid receptor gp250 precursor; glutamate-cysteine ligase regulatory subunit; inwardly rectifying potassium channel Kir3.2; aminopeptidase N; aminoacylase-l; B2-bradykinin receptor, 3; histidine ammonia-lyase; L-myc-l-proto-oncogene protein; YL-1 protein; fibrogen alpha chain precursor; thyroxin-binding globulin and globulin precursor; SPARC/osteonectin; alcohol dehydrogenase 1 alpha polypeptide; f~brinogen garnma-B chain Kurachi et al., 2002 RAB 1 la and RAB3D (members of RAS oncogene family) ; Ral-A protein; interferon-inducible GTPase; insulin-like grow~ factor binding protein 3 and ALS; calcium binding protein All; regucalcin; S100 calcium binding protein A1; cyclin dependent kinase inhibitor 1A; proteasome 26S subunit; proprotein convertase subtilison/kexin type 6; metaxin 2; ubiquitin-like 1; tyrosine 3-monooxygenase activation protein; Sin3-associated polypeptide; eukaryotic ~anslation initiation factor s 2 and 3; eukaryotic translation elongation factors 1 and 2; nucleobindin; heterogeneous nuclear ribonucleoproteins C and K; high mobility group protein 1; histone gene complex 1 ;YY1 transcription factor; zinc finger protein 207; upstream 42
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From page 43... ...
The findings in animals continue to indicate that reproductive, developmental, and oncogenic end points are very sensitive to TCDD. The data support the biologic plausibility of similar end points of toxicity in exposed humans.
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From page 44... ...
It is of interest that nuclear localization and transcriptional activation of the AhR have been found to occur in the absence of an exogenous ligand, such as TCDD (Richter et al., 2001~. That finding might indicate the existence of an endogenous ligand for the AhR whose identification would greatly increase our knowledge of AhR function and of how the inappropriate stimulation of the AhR by TCDD may lead to toxic effects.
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From page 45... ...
Notably, recent data indicate the association of an AhRR polymorphism (proline to leucine at the IS5 position) with micropenis in humans (Fujita et al., 2002~; this is particularly relevant because TCDD exposure to animals is known to affect the development of reproductive tissue.
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From page 46... ...
. Mechanisms Related to Particular Toxic End points As indicated in previous updates, an accumulation of studies in expenmental animals indicates that TCDD affects a variety of tissues, and the type of effect observed is often tissuespecific.
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Although the exact biochemical mechanisms of those end points and the observed differences are not yet understood, recent data have emphasized the possibility that at least some of the effects are mediated by TCDD's ability, through the AhR, to modulate cell-cycle control, signaling pathways that lead to cell death, hormones and growth factors and the responses to them, or the biochemical pathways that lead to oxidative stress (Barouki and Morel, 2001; Nebert et al., 2000~. Those mechanisms are implicated in many of the toxic end points discussed below.
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From page 48... ...
Mechanisms Related to Cardiovascular Toxicity There is a paucity of information on the potential for TCDD to exert toxic effects on the mammalian cardiovascular system. However, a recent study by Riecke et al.
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From page 49... ...
(2000) used synchrotron infrared spectromicroscopy to cletermine that TCDD exposure to human Iiver-tumor cells results in a relative increase in the number of methyl-methylene groups in single cells; this suggests an increase in DNA methylation and altered gene expression.
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From page 50... ...
may contribute to the oxidative damage observed after TCDD exposure. TCDD treatment of mice was found to increase reactive-oxygen production by liver mitochondria, and liver ATP concentrations were significantly decreased at the peak times of reactive-oxygen production (Senit et al., 2002~.
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Mechanisms Related to Carcinogenesis -As indicated in previous updates, TCDD has been demonstrated to be a potent tumor promoter in several mode} systems. Its ability to induce cell proliferation and to alter differentiation is believed to be an important factor in the mechanism of TCDD-induced carcinogenesis.
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From page 52... ...
The authors suggest that that might be the basis of some rodent bioassays that show a decrease in the incidence of mammary tumors after TCDD exposure. On the other hand, there is data cited in this and earlier updates to suggest that under some conditions TCDD exposure may increase the risk for the development of breast tumors (see below and "Biologic Plausibility" for Breast Cancer in Chapter 61.
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From page 53... ...
observed that TCDD partially inhibited 5a-dihydrotestosteroneinduced gene induction. Mechanisms Related to Effects on the Ovary Immature female rats treated with TCDD before gonadotropin-induced follicular development and ovulation have been shown to produce significantly fewer ova than untreated control animals.
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From page 54... ...
· O Mechanisms Related to Effects on the Mammary Gland Human breast-cancer cells have been useful for investigating the mechanisms of AhR signaling and the effects of TCDD on hormonally induced responses, especially responses to estrogen. Update 2000 reported that TCDD has been shown to block many estrogen-induced responses in human breast-cancer cells.
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From page 55... ...
A cells alteration of T(~'F-R nctivilv m~v non ~nntnh,~te to this suppression. Mechanisms Related to Other Endocrine Effects As indicated in previous updates, TCDD has b een shown to affect the thyroid and thyroid hormones in s everal animal species.
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From page 56... ...
Animals expressing no EGF did not develop cleft palate after maternal TCDD exposure. The lack of the EGF or TGF-oc genes, however, increased the incidence and severity of TCDD-induced hydronephrosis.
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From page 57... ...
Exposure at gestation day 15 appeared to be critical for the- inhibition of breast epithelial development. As indicated in the previous updates, several reports of studies in animals and exposed humans suggest that pennatal exposure to TCDD or dioxin-like chemicals may impair brain development.
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From page 58... ...
A large proportion ot the pups from mother rats exposed ~ day after bird to TCDD at 1,000 ~lg/kg body weight lacked their third molars (Lukinmaa et al., 2001~. However, in contrast with prevention of development of the lower third molars after in utero exposure, the molars missing after neonatal (lactational)
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From page 59... ...
for 30 weeks; continuous TCDD exposure might be required for their continued development. The study suggests that chronic oral exposure to TCDD can induce metaplasia and proliferative changes in the lung.
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From page 60... ...
A continuation of those studies (Ohsako et al., 2002) showed that TCDD exposure at 1 ~g/kg maternal body weight on gestation day 18 resulted in significant decreases in the urogenital complex and ventral prostatic weight and in urogen~talglans penis length (the length between the anterior end of the urethra and the glans penis)
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From page 61... ...
In a teratogenic study in which pregnant female mice were treated with TCDD at 24 ~g/kg body weight on gestation day 12, cleft palate and hydronephrosis were induced in the offspring (Bryant et al., 2001~. An evaluation of the role of epidermal growth factor (EGF)
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From page 62... ...
and house mites, TCDD exposure suppressed, rather than enhanced, immune response, as measured by immunoglobulin E ([gE) synthesis, and decreased immune-mediated lung disease (Luebke et al., 2001~.
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From page 63... ...
SUMMARY OF TOXICITY PROFILES This section synthesizes the experimental (lata on 2,4-D, 2,4,5-T, picloram, cacodylic acid, and TCDD reviewed in this and previous LAO reports, with a focus on recent data.
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From page 64... ...
The relationship of any of those effects to any disease outcomes in animals or humans, however, is unknown. Taken all together, the experimental data reviewed in this and previous reports indicate that 2,4-D is relatively nontoxic, with neurodevelopmental effects after neonatal exposure (at 100 mg/kg body weight per day)
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From page 65... ...
Some data indicate that cacodylic acid acts through induction of oxidative damage or damage to DNA, and it has been shown to affect microtubule networks at particular points in mitosis. A recent study demonstrated that cacodylic acid causes necrosis of the epithelium of the urinary bladder followed by regenerative hyperplasia, and other studies have found that cacodylic acid is a potent inducer of apoptosis (or programed cell death)
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From page 66... ...
After In utero exposure, however, even the effects at high doses are not straightforward: in utero TCDD exposure decreases performance in some learning and memory tasks but improves performance in other tasks. In animals, one of the most sensitive systems to TCDD is the immune system.
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From page 67... ...
Recent data also suggest that promotion of liver tumors by TCDD in female rats depends on continuous exposure. Data published since Update 2000 are consistent with the hypothesis that TCDD produces most 0 f, i f n ot all, i Is e ffects b y b inding t 0 a p rotein that regulates gene expression, the aryl hydrocarbon receptor (AhR)
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From page 68... ...
2002. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors.
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From page 69... ...
2002. Recruitment of the NcoA/SRC-l/pl60 family of transcriptional coactivators by the aryl hydrocarbon receptor nuclear complex.
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From page 70... ...
2001. Polymorphisms of human aryl hydrocarbon receptor (AhR)
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From page 71... ...
2001. Persistent, low-dose 2,3,7,8-tetrachlorodibenzo-pdioxin exposure: Effect on aryl hydrocarbon receptor expression in a dioxin-resistance model.
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Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency. Toxicology and Applied Pharmacology 168: 16~172.
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From page 73... ...
2000. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of cytochrome P450 lAl, the aryl hydrocarbon receptor, and aryl hydrocarbon receptor nuclear translocator in rat brain and pituitary.
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From page 74... ...
and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in benign and malignant gynaecological conditions.
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2002. Conditional expression of a constitutively active aryl hydrocarbon receptor in MCF-7 human breast cancer cells.
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From page 76... ...
2002. Effects of aryl hydrocarbon receptor null mutation and in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on prostate and seminal vesicle development in C57BL/6 mice.
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2001. Aryl hydrocarbon receptor-mediated activity of mutagenic polycyclic aromatic hydrocarbons determined using in vitro reporter gene assay.
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(2001~. Interactions between aryl hydrocarbon receptor (AhR)
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From page 79... ...
2000. Subcellular localization of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2.
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From page 80... ...
2000. The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis.
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From page 81... ...
2002. Expression of the mediators of dioxin toxicity, aryl hydrocarbon receptor (AHR)
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From page 82... ...
Evidence for involvement of an aryl hydrocarbon receptor response element in constitutive expression. The Journal of Biological Chemistry 275: 6770~776.
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From page 83... ...
2000. Conditional disruption of the aryl hydrocarbon receptor nuclear translocator (A~nt)
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From page 84... ...
2001. Transcriptional activation of cathepsin D gene expression by 17~-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition.
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From page 85... ...
2000. CrosstaLk between estrogen receptor a and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteosomes.
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From page 86... ...
Detailed descriptions of the study populations are in Chapter 2 of Veterans and Agent Orange (hereafter referred to as LAO)
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From page 87... ...
. For the sake of thoroughness, the discussions of specific health outcomes in Chapters ~9 include references to studies discussed in previous Agent Orange reports and new studies, but in making its conclusions, the committee focuses on the most recent update when multiple reports on the same cohorts and end points are available.
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From page 88... ...
(1999) examined the association between TCDD exposure and cause of death; it looked at specific health outcomes, including cancer (all and site-specific)
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From page 89... ...
Extension and follow-up studies compared potential exposure to TCDD with medicalexamination frequency and morbidity (Bond et al., 1983) , and reproductive outcomes after potential paternal TCDD exposure (Townsend et al., 1982~.
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From page 90... ...
PREPUBLICATION COPY- UNCORRECTED PROOF 1.0 mg/m3, and less than 0.1 mg/m3. For follow-up Tom 1983 to 1994, a new category of"very low" was added for jobs that had nondetectable exposure-monitor~ng concentrations or in which less than 50°/O of time was spent in a low-exposure area and no time was spent in a high-exposure area.
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From page 91... ...
, production workers in the fonmer Soviet Union involved in the production of 2,4-D (Bashirov, 1969) , factory workers in Prague who exhibited symptoms of TCDD toxicity 10 years after occupational exposure to 2,4,5-T (Paz~erova-Vej~upkova et al., 1981)
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From page 92... ...
Since Update 2000, three other studies have been identified that report reproductive outcomes from that questionnaire and that cohort. Savitz et al.
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From page 93... ...
, reproductive outcomes among male chemical appliers in New Zealand (Smith et al., 1981, 1982) , and doctor visits resulting from pesticide exposure in [owe and North Carolina (Alavanja et al., 19981.
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From page 94... ...
PREPUBLICATION COPY- UNCORRECTED PROOF herbicide appliers (Swaen et al., 1992) , cancer mortality among Minnesota highway-maintenance workers(Bender etal., 1989)
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From page 95... ...
studies have been conducted in venous US populations on other cancers, including NHL (Cantor, 1982; Cantor et al., 1992; Zahm et al., 1993; Tatham et al., 1997~; multiple myeloma (Morris et al., 1986; Boffetta et al., 1989; Brown et al., 1993~; cancers of He stomach and prostate, NHL, and multiple myeloma (Burmeister et al., 1983~; STS, HD, and NHL (Hoar et al., 1986~; NHL, and HD (Dubrow et al., 1988~; and STS and NHL (Woods et al., 1987; Woods and Polissar, 1989~. Other studies outside the United States have looked at cancer end points: ovarian cancer in the Piedmont region of Italy (Donna et al., 1984~; brain gliomas in two hospitals in Milan, Italy (Musicco et al., 1988~; STS and other cancers in the 15 regional cancer reg~stnes that constitute the National Cancer Register in England (Balarajan and Acheson, 1984~; STS and malignant lymphomas in the Victorian Cancer Registry of Australia (Smith and Christophers, 1992~; lymphoid cancer in Milan, Italy (LaVecchia et al., 1989~; STS among rice weeders in northern Italy (Vineis et al., 1986~; primary lung cancer among pesticide users in Saskatchewan (McDuffie et al., 19904; and renal-cell carcinoma in the Denmark Cancer Registry (Mellemgaard et al., 1994~.
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From page 96... ...
. __c, ~ -I Other studies looked at specific health effects associated with TCDD exposure among Seveso residents, including chioracne, birth defects, spontaneous abortion, and crude birth and death rates (Bisanti et al., 1980~; chioracne and peripheral nervous system conditions (Barbien et al., 1988~; hepatic enzyme-associated conditions (Ideo et al., 1982, 1985~; abnormal birth outcomes (Mastroiacovo et al., 1988~; cytogenetic abnormalities in maternal and fetal tissues (Teaching et al., 1983~; neurologic disorders (Boer)
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From page 97... ...
T he r eview a rticle i ncluded n ine reports that focus primarily on reproductive outcomes (Can et al., 1983a,b; Huong and Phuong, 1983; Khoa, 1983; Lang et al.7 1983a,b; Nguyen, 1983; Phnong and Huong, 1983; Trung and Chien, 1983~. Vietnamese researchers later published results of four additional studies conducted in Vietnam two focusing on reproductive abnormalities (Phuong et al., 1989a,b)
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From page 98... ...
In the studies, exposure measures fall on a crude scale from the individual exposures of Ranch Hands, as reflected in serum TCDD measurements, to service in Vietnam as a surrogate of TCDD exposure in some state studies. It should also be noted that a variety of comparison groups have been used for the veteran cohort studies: (a)
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From page 99... ...
VAO, Updateit996, Update~99S, VeteransandAger~tOrange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter referred to as Type 2 Diabetes) (IOM, 20003, and Update 2000 discuss reports and papers addressing this cohort in more detail.
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From page 100... ...
According to TCDD concentrations, the Ranch Hands ant! comparison subjects were categorized as having "background", "low", or "high" exposure.
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From page 101... ...
Study participants were identified as having possible, probable, or diagnosed peripheral neuropathy if one, two, or all three, respectively, of the following outcomes occurred bilaterally: absence of the Achilles reflex, abnormal vibration at the ankle, amd abnormal pin-peck reaction. Veterans who had a history of neurologic disorders before service in Southeast Asia, whose TCDD measurements were missing, who had conditions that would interfere with an assessment of the peripheral nerves, or who had specific necrologic disorders of known causes unrelated to TCDD exposure were excluded.
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From page 102... ...
(2001) studied the relationship between serum TCDD and cognitive function among the cohort of Ranch Hand veterans PreviouslY described in Wolfe et al.
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