TABLE 9-1 Epidemiologic Studies—Neural Tube Defects

Reference

Description

N

OR/RR (95% CI)

Occupational

No specific results for neural tube defects

 

 

Environmental

Hanify et al., 1981

Anencephaly

10

1.4 (0.6-3.3)

 

Spina bifida

13

1.1 (0.6-2.3)

Stockbauer et al., 1988

TCDD soil contamination in Missouri

 

 

 

Central nervous system defects

3

3.0 (0.3-35.9)

Vietnam veterans

Erickson, 1984a,b

Birth Defects Study

 

 

 

Vietnam veteran: spina bifida

19

1.1 (0.6-1.7)

 

Vietnam veteran: anencephaly

12

0.9 (0.5-1.7)

 

EOI-5: spina bifida

19a

2.7 (1.2-6.2)

 

EOI-5: anencephaly

7a

0.7 (0.2-2.8)

 

 

 

 

CDC, 1989

Vietnam Experience Study

 

 

 

Interview study Spina bifida

9

1.7 (0.6-5.0) among Vietnam veterans

 

 

5

among non-Vietnam veterans

 

Anencephaly

3

among Vietnam veterans

 

 

0

among non-Vietnam veterans

Australian veterans

Birth defects and father's Vietnam service (Australia)

 

 

Health Studies, 1983

Neural tube defects

16

0.9

AFHS, 1995

Follow-up of Air Force Ranch Hands Neural tube defects

4 among Ranch Handb 0 among comparison

NOTE: N = number of exposed cases; OR/RR = Odds Ratio/Relative Risk; CI = Confidence Interval; SIR = Standardized Incidence Ratio.

a Number of Vietnam veterans fathering a child with a neural tube defect given any exposure opportunity index score.

b Four neural tube defects among Ranch Hand offspring include 2 spina bifida (high dioxin level), 1 spina bifida (low-dioxin), and 1 anencephaly (low-dioxin). Denominator for Ranch Hand group is 792 liveborn infants.



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--> TABLE 9-1 Epidemiologic Studies—Neural Tube Defects Reference Description N OR/RR (95% CI) Occupational No specific results for neural tube defects     Environmental Hanify et al., 1981 Anencephaly 10 1.4 (0.6-3.3)   Spina bifida 13 1.1 (0.6-2.3) Stockbauer et al., 1988 TCDD soil contamination in Missouri       Central nervous system defects 3 3.0 (0.3-35.9) Vietnam veterans Erickson, 1984a,b Birth Defects Study       Vietnam veteran: spina bifida 19 1.1 (0.6-1.7)   Vietnam veteran: anencephaly 12 0.9 (0.5-1.7)   EOI-5: spina bifida 19a 2.7 (1.2-6.2)   EOI-5: anencephaly 7a 0.7 (0.2-2.8)         CDC, 1989 Vietnam Experience Study       Interview study Spina bifida 9 1.7 (0.6-5.0) among Vietnam veterans     5 among non-Vietnam veterans   Anencephaly 3 among Vietnam veterans     0 among non-Vietnam veterans Australian veterans Birth defects and father's Vietnam service (Australia)     Health Studies, 1983 Neural tube defects 16 0.9 AFHS, 1995 Follow-up of Air Force Ranch Hands Neural tube defects 4 among Ranch Handb 0 among comparison NOTE: N = number of exposed cases; OR/RR = Odds Ratio/Relative Risk; CI = Confidence Interval; SIR = Standardized Incidence Ratio. a Number of Vietnam veterans fathering a child with a neural tube defect given any exposure opportunity index score. b Four neural tube defects among Ranch Hand offspring include 2 spina bifida (high dioxin level), 1 spina bifida (low-dioxin), and 1 anencephaly (low-dioxin). Denominator for Ranch Hand group is 792 liveborn infants.

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--> Conclusions Strength of Evidence in Epidemiologic Studies There is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and spina bifida. There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides and all other birth defects. The evidence regarding association is drawn from occupation and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Biologic Plausibility Laboratory studies of the potential developmental toxicity, specifically birth defects, of TCDD and herbicides as a result of exposure to adult male animals are too limited to permit conclusions. Risk in Vietnam Veterans Since the strongest associations are from studies of Vietnam veterans and there are some data suggesting that the highest risks were for those veterans estimated to have had exposure to Agent Orange (e.g., Ranch Hands), it therefore follows that there is limited/suggestive evidence for an increased risk in Vietnam veterans of spina bifida in offspring. Childhood Cancer Background In most epidemiologic studies, childhood cancer usually refers to cancer diagnosed from birth through age 15. Childhood cancers are usually classified by primary anatomic site or tumor cell type. The distribution of childhood cancers by type includes leukemia (23 percent), lymphoma (13 percent), central nervous system (19 percent), neuroblastoma (8 percent), soft-tissue sarcoma (7 percent), kidney (6 percent), bone (5 percent), retinoblastoma (3 percent), liver (1 percent), and other (8 percent). There are approximately 6,500 new cases of cancer diagnosed each year in the United States in persons under age 15 (Young et al., 1986). About 2,200 deaths each year result from childhood cancer. Compared with adult cancers, relatively little is known about the etiology of most childhood cancers, and especially about potential environmental risk factors.

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--> Summary of VAO There are no available occupational and environmental epidemiologic studies of herbicide exposure that address childhood cancer as an outcome. Two studies of Vietnam veterans found some suggestion of an increased risk of cancer among offspring. The evidence is, however, inadequate, given the lack of other studies, failure to exclude chance and bias, and problems with herbicide exposure assessment. Update of Scientific Literature A mortality study conducted as part of the continuing follow-up of the possible health effects of the Seveso accident (see Chapter 6 for general description), suggested an increased risk of leukemia among children and young adults under age 20 (Bertazzi et al., 1992). This report led to a more detailed incidence study of cancer among young persons in the Seveso study groups (Pesatori et al., 1993). Specifically, the population for these analyses included subjects who were living in the study accident zones (A, B, R) and a reference (noncontaminated) area on the day of the accident and were between 0 and 19 years old during the first ten years afterward. Cases were identified from linkage of the study population subjects with the hospital discharge data from the Lombardy region. Medical records were reviewed to confirm diagnoses. The follow-up period was from 1977 through 1986. Owing to the small number of subjects in Zones A and B, the three zones were combined for analysis. Poison regression was used to compare the risk of cancer in the exposed study group (Zones A, B, and R) relative to the risk in the unexposed group. The vital status ascertainment and follow-up of the subjects was excellent, with vital status determined for 99 percent of the study group. At the end of follow-up, 95 percent of subjects were still living in the Lombardy area. A total of 17 cancers were found in the exposed study group from Zones A, B, and R. A total of 62 cases were detected in the reference population. Among the 17 cases, one was from zone A (the most exposed, 0.2 expected), two from Zone B (1.9 expected), and 14 were from Zone R (the least exposed). The overall relative risk was 1.2 (95 percent CI 0.7-2.1; 17 observed, 13.6 expected). When analyzed by site or type of cancer, there was a nearly fivefold increased risk of thyroid cancer (RR = 4.6; CI 0.6-32.7). Among hematological malignancies, a relative risk of 2 was found for Hodgkin's disease (CI 0.5-7.6), and a nearly threefold increased risk of myeloid leukemia was observed (3 observed, 1.1 expected; RR = 2.7; CI 0.7-11.4). An excess was also found for ovarian cancer (two observed versus none expected). No cancer was found among the 186 children who had chloracne diagnosed after the accident (expected = 0.2). As the authors acknowledged, the study had a number of limitations. A major concern was the small number of subjects, as reflected in the wide confidence

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--> intervals associated with the relative risk estimates. This forced the investigators to combine the three exposed zones into one group for analysis. A serious concern with the Seveso studies in general is the fact that exposure is ecological, and all subjects were assigned to one of three exposure groups based on area of residence. Thus, results from the Seveso study suggest an increased risk of some types of childhood cancer among potentially exposed residents. As described in VAO report, the CDC Vietnam Experience Study found an elevated relative risk estimate for childhood leukemia (OR = 1.6; CI 0.6-4.0) (Centers for Disease Control, 1989). The specific types of leukemia found were not reported. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides considered in this report and childhood cancer. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Conclusions For Reproductive Effects Strength of Evidence in Epidemiologic Studies There is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and spina bifida. There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides and infertility, spontaneous abortion, stillbirth, birth defects (other than spina bifida), and childhood cancer. Biologic Plausibility Experimental animal evidence indicates that dioxin can alter gonadotrophin and testosterone levels, but generally at relatively high doses. Laboratory studies of herbicides and male-mediated developmental endpoints such as birth defects and cancer are too limited to permit conclusions. Increased Risk of Disease among Vietnam Veterans Since there are some data suggesting that the highest risks occur in those veterans estimated to have had exposure to Agent Orange (e.g., Ranch Hands), it

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--> therefore follows that there is limited/suggestive evidence for an increased risk of spina bifida among offspring of Vietnam veterans. Given the large uncertainties that remain about the magnitude of potential risk of infertility, spontaneous abortion, stillbirth, birth defects (other than spina bifida), and childhood cancer from exposure to herbicides in the studies that have been reviewed, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. References Ahlborg G, Hogstedt C, Bodin L, Barany S. 1989. Pregnancy outcome among working women. Scandinavian Journal of Work, Environment, and Health 15:227-233. Air Force Health Study. 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides . Reproductive Outcomes. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1992-0090. Air Force Health Study. 1995. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Follow-up Examination Results. 10 vols. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. Aschengrau A, Monson RR. 1990. Paternal military service in Vietnam and the risk of late adverse pregnancy outcomes. American Journal of Public Health 80:1218-1224 Australia Department of Veterans Affairs. 1983. Case-Control Study of Congenital Abnormalities and Vietnam Service. Canberra, Australia: Department of Veterans Affairs. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Consonni D, Tironi A, Landi MT. 1992. Mortality of a young population after accidental exposure to 2,3,7,8-tetrachlorodibenzo dioxin. International Journal of Epidemiology 21:118-123. Bloom AD, ed. 1981. Guidelines for Studies of Human Populations Exposed to Mutagenic and Reproductive Hazards. White Plains, New York: March of Dimes Foundation. Centers for Disease Control. 1988. Health status of Vietnam veterans. III. Reproductive outcomes and child health. Journal of the American Medical Association 259:2715-2717. Centers for Disease Control. 1989. Health status of Vietnam veterans. Vietnam Experience Study. Atlanta: U.S. Department of Health and Human Services. Vols. I-V, Supplements A-C. Constable JD, Hatch MC. 1985. Reproductive effects of herbicide exposure in Vietnam: recent studies by the Vietnamese and others. Teratogenesis, Carcinogenesis, and Mutagenesis 5:231-250. Deprez RD, Carvette ME, Agger MS. 1991. The health and medical status of Maine veterans: a report to the Bureau of Veterans Services Commission of Vietnam and Atomic Veterans. Donovan JW, MacLennan R, Adena M. 1984. Vietnam service and the risk of congenital anomalies: a case-control study. Medical Journal of Australia 140:394-397. Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr TM, Halperin WE. 1994. Total serum testosterone and gonadotrophins in workers exposed to dioxin. American Journal of Epidemiology 139:272-281. Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr TM, Halperin WE . 1995. Reply to letter to the editor. American Journal of Epidemiology 141:477-478 Erickson J, Mulinare J, Mcclain P, Fitch T, James L, McClearn A, Adams M. 1984a. Vietnam Veterans' Risks for Fathering Babies with Birth Defects. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control. Erickson JD, Mulinare J, Mcclain PW. 1984b. Vietnam veterans' risks for fathering babies with birth defects. Journal of the American Medical Association 252:903-912.

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--> Fenster L, Coye MJ. 1990. Birthweight of infants born to Hispanic women employed in agriculture. Archives of Environmental Health 45:46-52. Field B, Kerr C. 1988. Reproductive behaviour and consistent patterns of abnormality in offspring of Vietnam veterans. Journal of Medical Genetics 25:819-826. Fitzgerald EF, Weinstein AL, Youngblood LG, Standfast SJ, Melius JM. 1989. Health effects three years after potential exposure to the toxic contaminants of an electrical transformer fire. Archives of Environmental Health 44:214-221. Gordon JE, Shy CM. 1981. Agricultural chemical use and congenital cleft lip and/or palate. Archives of Environmental Health 36:213-221. Goulet L, Theriault G. 1991. Stillbirth and chemical exposure of pregnant workers. Scandinavian Journal of Work, Environment, and Health 17:25-31. Hanify JA, Metcalf P, Nobbs CL, Worsley KJ. 1981. Aerial spraying of 2,4,5-T and human birth malformations: an epidemiological investigation. Science 212:349-351. Hemminki K, Mutanen P, Luoma K. 1980. Congenital malformations by the parental occupation in Finland. International Archives of Occupational and Environmental Health 46:93-98. Jansson B, Voog L. 1989. Dioxin from Swedish municipal incinerators and the occurrence of cleft lip and palate malformations. International Journal of Environmental Studies 34:99-104. Kallen B. 1988. Epidemiology of Human Reproduction. Boca Raton: CRC Press. Kalter H, Warkany J. 1983. Congenital malformations. Etiologic factors and their role in prevention (first of two parts). New England Journal of Medicine 308:424-491. Kline J, Stein Z, Susser M. 1989. Conception to Birth: Epidemiology of Prenatal Development. New York: Oxford University Press. Knobil E, Neill JD, Greenwald GS, Markert CL, Pfaff DW, (eds). 1994. The Physiology of Reproduction. New York: Raven Press. Lewis W, Mekdeci B. 1993. Birth Defect/Learning Disabilities Registry and Database. New Jersey Agent Orange Commission, Association of Birth Defect Children. Submitted to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Agent Orange. Mastroiacovo P, Spagnolo A, Marni E, Meazza L, Bertollini R, Segni G, Borgna-Pignatti C. 1988. Birth defects in the Seveso area after TCDD contamination [published erratum appears in JAMA 1988:260(6):792]. Journal of the American Medical Association 259:1668-1672. McDonald AD, McDonald JC, Armstrong B. 1987. Occupation and pregnancy outcome. British Journal of Industrial Medicine 44:521-526. Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. American Journal of Industrial Medicine 5:161-182. Nelson CJ, Holson JF, Green HG, Gaylor DW. 1979. Retrospective study of the relationship between agricultural use of 2,4,5-T and cleft palate occurrence in Arkansas. Teratology 19:377-383. Ng TP, Goh HH, Ng YL, Ong HY, Ong CN, Chia KS, Chia SE, Jeyaratna M. 1991. Male endocrine functions in workers with moderate exposure to lead. British Journal of Industrial Medicine 48:485-491. Nurminen T, Rantala K, Kurppa K, Holmberg PC. 1994. Agricultural work during pregnancy and selected structural malformations in Finland . Epidemiology 1: 23-30 Pesatori AC, Consonni D, Tironi A, Zocchetti C, Fini A, Bertazzi PA. 1993. Cancer in a young population in a dioxin-contaminated area. International Journal of Epidemiology 22:1010-1013. Phuong NTN, Thuy TT, Phuong PK. 1989. An estimate of reproductive abnormalities in women inhabiting herbicide sprayed and non-herbicide sprayed areas in the south of Vietnam, 1952-1981. Chemosphere 18:843-846. Rellahan W. 1985. Aspects of the Health of Hawaii's Vietnam-era Veterans. Honolulu: Hawaii State Department of Health, Research and Statistics Office.

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--> Restrepo M. Munoz N, Day NE, Parra JE, Hernandez C, Brettner M, Giraldo A. 1990. Prevalence of adverse reproductive outcomes in a population occupationally exposed to pesticides in Colombia. Scandinavian Journal of Work, Environment, and Health 16:232-238. Roegner RH, Grubbs WD, Lustik MB, Brockman AS, Henderson SC, Williams DE, Wolfe WH, Michalek JE, Miner JC. 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Follow-up Examination Results. NTIS AD A-237-516 through AD A-237-524: San Antonio: Armstrong Laboratory, Brooks Air Force Base. Savitz DA, Whelan EA, Kleckner RC. 1989. Effect of parents' occupational exposures on risk of stillbirth, preterm delivery, and small-for-gestational-age infants. American Journal of Epidemiology 129:1201-1218. Smith AH, Fisher DO, Pearce N, Chapman CJ. 1982. Congenital defects and miscarriages among New Zealand 2,4,5-T sprayers. Archives of Environmental Health 37:197-200. Stockbauer JW, Hoffman RE, Schramm WF, Edmonds LD. 1988. Reproductive outcomes of mothers with potential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Epidemiology 128:410-419. Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251:2372-2380. Townsend JC, Bodner KM, Van Peenen PFD, Olson RD, Cook RR. 1982. Survey of reproductive events of wives of employees exposed to chlorinated dioxins. American Journal of Epidemiology 115:695-713. Wendt AS. 1985. Iowa Agent Orange survey of Vietnam veterans. Iowa State Department of Health. White FMM, Cohen FG, Sherman G, McCurdy R. 1988. Chemicals, birth defects and stillbirths in New Brunswick: associations with agricultural activity. Canadian Medical Association Journal 138:117-124. Whorton MD, Milby TH, Krauss RM. 1979. Testicular function in DBCP exposed pesticide workers. Journal of Occupational Medicine 21:161-166. Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC. 1988. Incidence of early loss of pregnancy. New England Journal of Medicine 319:189-194. Wolfe WH, Michalek JE, Miner JC, Roegner RH, Grubbs WD, Lustik MB, Brockman AS, Henderson SC, Williams DE. 1992. The Air Force health study: an epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides, serum dioxin analysis of 1987 examination results. Chemosphere 25:213-216. Wolfe WH, Michalek JE, Miner JC, Rahe AJ, Moore CA, Needham LL, Patterson DG Jr. 1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand. Epidemiology 6:17-22. World Health Organization. 1977. Recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths (modifications recommended by FIGO as amended October 14, 1976). Acta Obstetrica et Gynecologica Scandinavica 56:247-253. Yen SC, Jaffe RB. 1991. Reproductive Endocrinology. Philadelphia: WB Saunders Company. Young JL, Ries LG, Silverberg E, Horm JW, Miller RW. 1986. Cancer incidence, survival, and mortality for children younger than age 15 years. Cancer 58:598-602.

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--> 10 Neurobehavioral Disorders Introduction Neurologic problems in clinical medicine cover a wide variety of disorders. The nervous system is anatomically and functionally divided into central and peripheral subsystems. The central nervous system (CNS) includes the brain and spinal cord, and CNS dysfunction can be subdivided into two general categories: neurobehavioral and motor/sensory. Neurobehavioral difficulties involve two primary categories: cognitive decline, including memory problems and dementia; and neuropsychiatric disorders, including neurasthenia (a collection of symptoms including difficulty concentrating, headache, insomnia, and fatigue), depression, posttraumatic stress disorder (PTSD), and suicide. Other CNS problems can be associated with motor difficulties, characterized by problems such as weakness, tremors, involuntary movements, incoordination, and gait/walking abnormalities. These are usually associated with subcortical or cerebellar system dysfunction. The anatomic elements of the peripheral nervous system (PNS) include the spinal rootlets that exist the spinal cord, the brachial and lumbar plexus, and the peripheral nerves that innervate the muscles of the body. PNS dysfunctions, involving either the somatic nerves or the autonomic system, are known as neuropathies. Neurologic dysfunction can be further classified, based on anatomic distribution, as either global or focal; temporal onset, as acute, subacute, or chronic; or temporal course, as transient or persistent. For example, global cerebral dysfunction may lead to altered levels of consciousness, whereas focal lesions cause isolated signs of cortical dysfunction, such as aphasia. Acute onset of motor/coordination disturbances leads to symptoms that develop over minutes or hours,

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--> whereas subacute onset occurs over days or weeks and chronic onset over months or years. Finally, transient peripheral neuropathies resolve spontaneously, whereas persistent ones may lead to chronic deficits. In the original report, VAO, attention was deliberately focused on persistent neurobehavioral dysfunction. In the present report, all new data pertinent to clinical neurobehavioral dysfunction are reviewed; in addition, at the specific request of the Department of Veterans Affairs (DVA), earlier data relating to transient acute and subacute peripheral neuropathy are reexamined. Case identification in neurology is often difficult. Despite advances in neuroimaging, many types of neurologic alterations are biochemical and show no abnormalities on scanning tests. The nervous system is not usually accessible for biopsy, so pathologic confirmation is not feasible for many neurologic disorders. Behavioral and neurophysiologic changes can be partly or largely subjective and, even when objectively documented, may often be reversible. Timing is important in assessing the effect of chemical exposures on neurologic function. Some symptoms of neurologic importance will appear acutely but be short-lived, whereas others will appear slowly and be detectable for extended periods. These caveats must be considered in the design and critique of epidemiologic studies evaluating an association between exposure to any chemical agent and neurologic or neurobehavioral dysfunction. Many reports have addressed the possible contribution of herbicides and pesticides to nervous system dysfunction, and reported abnormalities have ranged from mild and reversible to severe and long-standing. These assessments have been conducted in three general settings, related to occupational, environmental, and Vietnam veteran exposures (see Table 10-1). Several case reports of patients ingesting 2,4-dichlorophenoxyacetic acid (2,4-D) are mentioned under environmental exposures. This chapter reviews reports of neurologic alterations associated with exposure to herbicides, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), or other compounds used in herbicides in Vietnam. The chapter emphasizes the small number of cross-sectional studies with comparison samples in which both exposed and unexposed persons were neurologically assessed by systematic physical examinations and/or ancillary tests, such as neuropsychological evaluations or EMG measurements. The potential neurotoxicity of TCDD and herbicides in animal studies has not been thoroughly investigated (see Chapter 3). A large number of acute and subchronic toxicity studies have been conducted with TCDD, but the majority of these studies were not designed specifically to investigate neurotoxicity. Available data imply that CNS alterations or changes in the responsiveness of neurochemical processes in the CNS may be associated with lethal or near-lethal dose levels of TCDD in some animal species; however, the changes observed may also be regulatory responses occurring secondary to changes induced in other organ systems. TCDD concentrations in the brain after systemic exposure are low, and are quite similar among rodent species. Relatively little work has been done to

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--> TABLE 10-1 Selected Neurobehavioral Studies of Herbicide Exposure   Study Group N Tests of Neurological Dysfunction Exposure Measures Comparison Group Environmental Peper et al., 1993 19 German residents exposed to 2,3,7,8-TCDD Neuropsychological battery and symptom questionnaires Serum TCDD None Occupational Zober et al., 1994 158 German BASF employees Medical record review Chloracne and TCDD levels 161 reference comparisons Baader and Bauer, 1951 10 pentachlorophenol plant workers Record review Clinical evaluation No None Goldstein et al., 1959 2 farmers 1 bookkeeper Neurological examination; EMG No None Todd, 1962 1 weed-sprayer Neurological examination No None Berkley and Magee, 1963 1 farmer Neurological examination No None Vietnam Decoufle et al., 1992 7,924 veterans Self-report with neurological examinations in a subset Self-report 7,364 non-Vietnam veterans Visintainer et al., 1995 151,377 Michigan veterans who served in Vietnam No: mortality data only No 225,651 Non-Vietnam veterans

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--> quantify the concentration of Ah receptors in the central or peripheral nervous systems. Cognitive And Neuropsychiatric Effects Summary of VAO In VAO, the committee concluded that the literature was insufficient to determine whether an association existed between exposure to herbicides and related compounds and chronic cognitive or neuropsychiatric disorders. As suggested by Sharp et al. (1986), the delayed effects of such exposures on human health are difficult to detect, and the health risks may be sufficiently small that they are below the power of present epidemiologic studies to detect. Although there was no shortage of studies concerning this topic, methodologic problems made it difficult to reach definitive conclusions. Shortcomings in defining exposure included absent or poor exposure assessments; inconsistencies in identifying exposed individuals for study (i.e., some studies relied upon the presence of chloracne for inclusion, while others assumed that all subjects were exposed); and concomitant exposure to different chemicals, mixtures of chemicals, or concentrations of chemicals. Studies of cognitive or neuropsychiatric disorders are also weakened by the small numbers of subjects; poor selection or absence of comparison groups; confounding of the possible effects of herbicides with the effects of stress; and inadequate statistical analyses. Self-reports of exposure and symptoms may not be verified independently. The committee noted that in order to maximally define the direct effects of dioxin on cognitive and neuropsychiatric function, future studies should focus primarily on occupationally exposed groups for whom levels of exposure were better known and should include neurobehavioral testing in relative proximity to the time of exposure. VAO also concluded that significantly exposed subjects should be followed for the development of neuropsychological dysfunction in middle and later life. It is possible that minor CNS changes acquired in early adulthood were too subtle to be detected by current neuropsychological testing methods, but they could manifest themselves later when compounded by ''normal age-related changes" of the CNS. Theoretically, exposure to neurotoxins could produce "accelerated aging" of the brain due to premature neuronal loss, which could then result in neurobehavioral deficits. Update of the Scientific Literature Several papers on this topic have appeared since VAO. In the study by Peper et al. (1993) of chronic exposure to environmental polychlorinated dibenzodioxins and dibenzofurans (PCDD/PCDF) at high and low exposures, the group with