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Appendix B
Short-Term Adverse Health Responses
As was indicated to be the intention of the committee responsible for Update
2008, the committee for Update 2010 has removed chloracne, porphyria cutanea
tarda (PCT), and early-onset peripheral neuropathy from the body of these Vet -
erans and Agent Orange (VAO) reports. The three conditions that occur in tem -
poral proximity to exposure have little relevance for new claims from Vietnam
veterans, and there has been minimal new evidence since they were classified as
having evidence of an association with herbicide exposure
The three conditions have long been recognized by the Department of Vet-
erans Affairs as presumptively related to service in Vietnam. Consequently, the
committee wants to provide easy access to the body of biomedical evidence on
which these decisions were made by retaining the information distilled in this ap-
pendix and in the corresponding appendixes in future volumes in the VAO series.
CHLORACNE
Chloracne is a skin disease that is characteristic of exposure to 2,3,7,8-tetra -
chlorodibenzo-p-dioxin (TCDD) and other diaromatic organochlorine chemicals.
It shares some pathologic processes (such as the occlusion of the orifice of the
sebaceous follicle) with more common forms of acne (such as acne vulgaris),
but it can be differentiated by the presence of epidermoid inclusion cysts, which
are caused by proliferation and hyperkeratinization (horn-like cornification) of
the epidermis and sebaceous gland epithelium. Although chloracne is typically
distributed over the eyes, ears, and neck, it can also occur on the trunk, genitalia,
and buttocks of chemical-industry workers exposed to TCDD (Neuberger et al.,
1998). It is resistant to acne treatments, but it usually regresses.
777
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778 VETERANS AND AGENT ORANGE: UPDATE 2010
Chloracne has been used as a marker of exposure in epidemiologic studies
of populations exposed to TCDD and related chemicals. It is one of the few find -
ings in humans that are consistently associated with such exposure, and it is a
well-validated indicator of high-dose exposure to TCDD and related chemicals
(Sweeney et al., 1997/98). If chloracne occurs, it appears shortly after the chemi -
cal exposure, not after a long latent period; therefore, new cases of chloracne
among Vietnam veterans would not be the result of exposure during the Vietnam
War. It should be noted that absence of chloracne does not necessarily indicate ab-
sence of substantial exposure to TCDD, as is apparent from studies of people who
had documented exposure to TCDD after the Seveso incident (Baccarelli et al.,
2005a), nor is there necessarily a correlation between serum TCDD concentration
and the occurrence or severity of chloracne. Susceptibility to the development of
chloracne varies among individuals.
Conclusions from VAO and Previous Updates
The committee responsible for Veterans and Agent Orange: Health Effects
of Herbicides Used in Vietnam (referred to as VAO; IOM, 1994) determined that
there was sufficient evidence of an association between exposure to at least one
chemical of interest (TCDD) and chloracne. Additional information available to
the committees responsible for Veterans and Agent Orange: Update 1996 (IOM,
1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002
(IOM, 2003), Update 2004 (IOM, 2005), and Update 2006 (IOM, 2007) has not
modified that conclusion.
Even in the absence of full understanding of the cellular and molecular
mechanisms that lead to the disease, several notable reviews (Panteleyev and
Bickers, 2006; Sweeney and Mocarelli, 2000) have deemed the clinical and
epidemiologic evidence of dioxin-induced chloracne to be strong. The occupa -
tional epidemiologic literature has many examples of chloracne in workers after
reported industrial exposures (Beck et al., 1989; Bond et al., 1987, 1989a,b;
Cook et al., 1980; Goldman, 1972; May, 1973, 1982; Oliver, 1975; Pazderova-
Vejlupkova et al., 1981; Poland et al., 1971; Suskind and Hertzberg, 1984;
Suskind et al., 1953; Zober et al., 1990). With relative-risk estimates as high as
5.5 in exposed workers compared with referent nonexposed workers, Bond et al.
(1989a) identified a dose–response relationship between probable exposure to
TCDD and chloracne. Not everyone exposed to relatively high doses develops
chloracne, and some with lower exposure may acquire it (Beck et al., 1989).
Almost 200 cases of chloracne were recorded in those residing in the vicinity
of the accidental industrial release of dioxin in Seveso, Italy. Most cases occurred
in children, particularly in people who lived in the highest-exposure zone, and
most cases resolved within 7 years (Assennato et al., 1989a,b; Caramaschi et al.,
1981; Mocarelli et al., 1991). No cases of chloracne were identified in conjunc -
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APPENDIX B
tion with the nonextreme environmental dioxin contamination at Times Beach,
Missouri (Webb et al., 1987).
Exposures of Vietnam veterans were substantially lower than those observed
in occupational studies and in environmental disasters, such as the one in Seveso.
The long period since the putative exposure has imposed methodologic limita -
tions on studies of Vietnam cohorts for chloracne. Nonetheless, the Vietnam
Experience Study (CDC, 1988) found that chloracne was self-reported more
often by Vietnam veterans than by Vietnam-era veterans (odds ratio [OR] = 3.9).
An excess incidence was also found in Vietnam vs era veterans among subjects
who were physically examined (OR = 7.3). In comparison with a nonexposed
group, Air Force Ranch Hand personnel potentially exposed to Agent Orange
reported a significant excess of acne (OR = 1.6) (Wolfe et al., 1990), but no cases
of chloracne or postinflammatory scars were found on physical examination 20
years after possible herbicide exposure (AFHS, 1991b).
Biologic Plausibility
Previous updates have reported that chloracne-like skin lesions have been
observed in several animal species in response to exposure to TCDD but not to
purified phenoxy herbicides. Data accruing over the past several decades demon -
strated that TCDD alters differentiation of human keratinocytes, and more recent
studies have illuminated how. Geusau et al. (2005) found that TCDD accelerates
the events associated with early differentiation but also obstructs completion of
differentiation. Panteleyev and Bickers (2006) proposed that the major mecha -
nism of TCDD induction of chloracne is activation of the stem cells in the basal
layer of the skin to differentiate and inhibition of their ability to commit fully
to a differentiated status. Ikuta et al. (2010) have investigated the expression of
B-lymphocyte maturation protein 1 (Blimp1) in epidermal keratinocytes and
sebocytes in mice after induction of the aryl hydrocarbon receptor (AHR). Re -
cent work with a constitutively activated form of the AHR implicated additional
inflammation-related mechanisms by which TCDD exposure may lead to chlor-
acne (Tauchi et al., 2005). The data provide a biologically plausible mechanism
for the induction of chloracne by TCDD.
Synthesis
No epidemiologic data in the past decade have refuted the conclusion of prior
VAO committees that the evidence of an association between exposure to dioxin
and chloracne is sufficient. The 2004 poisoning case of Ukrainian politician
Victor Yuschenko has provided a high-profile instance that supports this condi -
tion as a response to high-level exposure to TCDD, and the careful monitoring
of his case has demonstrated the course of chloracne’s resolution in conjunction
with subsiding serum concentrations (Sorg et al., 2009). The formation of chlor-
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780 VETERANS AND AGENT ORANGE: UPDATE 2010
acne lesions after administration of TCDD has been observed in some species of
laboratory animals.
Conclusion
On the basis of numerous epidemiologic studies of occupationally and
environmentally exposed populations and supportive toxicologic information,
previous VAO committees have consistently concluded that there is sufficient
evidence of an association between exposure to at least one chemical of interest
and chloracne. Because TCDD-associated chloracne becomes evident shortly
after exposure, there is no risk of new cases long after service in Vietnam. Given
the established relationship of an association between TCDD and chloracne and
the long period that has elapsed since service in Vietnam, the present committee
concludes that the emergence of additional biologic or epidemiologic evidence
that would merit review and deliberation by later VAO committees is unlikely.
PORPHYRIA CUTANEA TARDA
Porphyrias are uncommon disorders caused by deficiencies of enzymes in-
volved in the pathway of biosynthesis of heme, the iron-containing nonprotein
portion of the hemoglobin molecule. PCT, the most common of the porphyrias, is
a heterogeneous group of disorders caused by a deficiency of a specific enzyme,
uroporphyrinogen decarboxylase. It, can be inherited but usually is acquired.
Type I PCT, which accounts for 80–90% of all cases, is an acquired disease that
typically becomes evident in adulthood. It can occur spontaneously but usually
occurs in conjunction with environmental factors, such as alcohol consumption,
exposure to estrogens, or use of some medications.
The most important clinical finding in PCT is cutaneous photosensitivity.
Sensitivity to sunlight is thought to result from the excitation of excess porphy -
rins in the skin by long-wave ultraviolet radiation, which leads to cell damage.
Fluid-filled vesicles and bullae develop on sun-exposed areas of the face and
on the dorsal surfaces of the hands, feet, forearms, and legs. Other features in -
clude hypertrichosis (excess hair) and hyperpigmentation (increased pigment),
especially on the face. People with PCT have increased porphyrins in the liver,
plasma, urine, and stools. Iron, estrogens, alcohol, viral hepatitis, and chlorinated
hydrocarbons can aggravate the disorder. Iron overload is almost always present
in people who have PCT.
Conclusions from VAO and Previous Updates
On the basis of strong animal studies and case reports demonstrating TCDD-
induced PCT and resolution after cessation of exposure, the committee respon -
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APPENDIX B
sible for VAO determined that there was sufficient evidence of an association
between exposure to TCDD and PCT in genetically susceptible people.
Epidemiologic studies of occupational populations have indicated incon-
sistent associations between the chemicals of interest and increased urinary
uroporphyrin. Bleiberg et al. (1964) reported increased urinary uroporphyrin in
11 of 29 workers in a factory that manufactured 2,4-dichlorophenoxyacetic acid
(2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and the manifestation
of some clinical evidence of PCT in three of them. In a follow-up study of the
same facility 6 years later, no abnormalities in urinary porphyrins were observed
(Poland et al., 1971). Calvert et al. (1992) reported no difference in porphyrin -
uria or the occurrence of PCT between 281 workers in the National Institute
for Occupational Safety and Health (NIOSH) cohort who were involved in the
production of trichlorophenol and were exposed to TCDD and 260 nonexposed
workers. Serum TCDD concentration was not associated with uroporphyrin or
coproporphyrin concentrations.
Among people who were exposed to TCDD as a result of the 1976 chemical-
plant explosion in Seveso, Italy, clinical PCT was observed only in a brother and
a sister who had a mutant enzyme that confers susceptibility in the heterozygous
state. In 1977, 60 Seveso residents were tested for increased porphyrins, and 13
had secondary coproporphyrinuria; increased concentrations persisted in only
three cases that were thought to be due to liver damage and alcohol consumption
(Doss et al., 1984). In the Quail Run mobile-home park in Missouri, residents ex-
posed to dioxin as a result of the spraying of waste oil contaminated with TCDD
were found to have higher urinary uroporphyrins than controls, but no cases of
clinical PCT were diagnosed (Hoffman et al., 1986; Stehr-Green et al., 1987).
The baseline study of the US Air Force Ranch Hands (AFHS, 1984) showed
no difference in uroporphyrin or coproporphyrin concentrations in urine between
Ranch Hands and controls. There were no indications of the clinical appearance
of PCT in Ranch Hands. Followup studies of the Ranch Hand cohort revealed
that mean uroporphyrin was greater in the comparison group than in the Ranch
Hands, whereas mean coproporphyrin was higher in Ranch Hands. The clinical
significance of the small differences between the Ranch Hands and the compari -
son groups was uncertain.
The committee responsible for Update 1996 considered three additional
nonpositive citations of populations that had substantial exposure to TCDD. Jung
et al. (1994) presented porphyrin data on former workers in a German pesticide
plant that had manufactured 2,4-D and 2,4,5-T. Of 170 men tested, 27 had pres-
ent or past chloracne. The study found no difference in porphyrin concentrations
between subjects with and without chloracne. There was also no relationship be -
tween abnormal results of liver-function tests or porphyrin concentrations and the
presence of chloracne. Additionally, there was no relationship between porphyrin
concentrations in urine, red blood cells, or plasma and TCDD concentrations in
adipose tissue. Three cases of chronic hepatic porphyria (none with overt PCT
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782 VETERANS AND AGENT ORANGE: UPDATE 2010
and none with chloracne) were identified—a number that did not exceed the
expected prevalence in this population. Von Benner et al. (1994) found no indica -
tion of clinical porphyria in self-referred workers at six other German chemical
plants. Another report on the NIOSH cohort (Calvert et al., 1994) was negative.
On the basis of the cumulative findings, the committee responsible for Update
1996 concluded that there was only limited or suggestive evidence of an associa-
tion. The committees for later updates have not changed the revised conclusion.
Because PCT is manifested shortly after exposure to TCDD, new cases of
PCT attributable to exposure during the Vietnam War are not expected to occur.
Biologic Plausibility
PCT has not been exactly replicated in animal studies on the effects of
TCDD although other porphyrin abnormalities have been reported. Administra -
tion of TCDD to mice results in an accumulation of uroporphyrin that occurs in
a manner that requires the AHR, cytochrome P450 1A1 (CYP1A1), and CYP1A2
(Robinson et al., 2002; Smith et al., 2001; Uno et al., 2004), but the underlying
mechanism of action has not been fully illuminated (Smith and Chernova, 2009;
Smith and Elder, 2010).
Synthesis
No epidemiologic data have emerged in the last decade that refute the con-
clusion of previous VAO committees that there is limited or suggestive evidence
of an association between the chemicals of interest and PCT.
Conclusion
On the basis of the evidence reviewed here and in previous VAO reports, the
committee concludes that there is limited or suggestive evidence of an association
between exposure to at least one chemical of interest and PCT. The occurrence
of PCT is rare and may be influenced by genetic predisposition in people who
have low concentrations of protoporphyrinogen decarboxylase. Because TCDD-
associated changes in porphyrin excretion become evident shortly after exposure,
there is no risk that new cases will occur long after service in Vietnam. Given
the recognized association between TCDD and porphyrin excretion and the long
period that has elapsed since service in Vietnam, the committee concludes that the
emergence of additional biologic and epidemiologic evidence that would merit
review and deliberation by later VAO committees is unlikely.
EARLY-ONSET PERIPHERAL NEUROPATHY
Since Update 1996, VAO committees have partitioned their consideration
of peripheral neuropathy into two categories: early-onset (implicitly transient)
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APPENDIX B
peripheral neuropathy and chronic peripheral neuropathy. Primarily on the basis
of reports of short-term health effects after industrial accidents, the committee
concluded in 1996 that there was limited or suggestive evidence of an association
between exposure to the chemicals of interest and “acute and subacute” neu -
ropathy, which was redesignated early-onset transient peripheral neuropathy by
the committee responsible for Update 2004. The present committee recognized
the imprecision in the nomenclature that has been used to characterize the type
of peripheral neuropathy that is regarded as service-connected. The diagnosis
in question is, in fact, contingent on the proximity of its occurrence to the time
of exposure, rather than on the transitory nature of the adverse outcome. Clini-
cally, in cases of an immediate response of peripheral neuropathy after toxicant
exposure, stabilization or improvement is the rule after exposure ends. However,
recovery may not be complete; the degree of recovery can depend on the sever-
ity of the initial deficits and the particular exposure. Furthermore, there is a
possibility of “subclinical” effects, and a person might be unaware of symptoms
although evidence of nerve dysfunction can be found through detailed neurologic
examination or electrodiagnostic testing. Thus, the committee chose to delete the
word transient to recognize that symptoms of early-onset peripheral neuropathy
may be protracted and that recovery from these symptoms may be incomplete.
The information about peripheral neuropathy presented in this appendix
demonstrates that this outcome may occur soon after exposure to extremely high
concentrations of dioxin. In addition, this appendix addresses the evidence that,
in populations with members who experience early-onset peripheral neuropathy
(that is, during or shortly after dioxin exposure), some may continue to manifest
the problem long after exposure has ceased, and this would show that early-onset
peripheral neuropathy is not necessarily transient.
Conclusions from VAO and Previous Updates
Several occupational studies have evaluated whether herbicide exposure or
production may lead to early-onset neuropathy. In March 1949, an explosion
occurred in a reactor vessel at a chemical plant in Nitro, West Virginia, where
2,4,5-T was being produced. Many workers reported health effects (toxic hepati -
tis, increased serum lipids, and central nervous system involvement), including a
severe acute neuropathy in four workers with chloracne (Ashe et al., 1949, 1950).
Thirty years later, an attempt was made to identify workers who had been ex-
posed during that accident and workers who may have been chronically exposed
from 1948 through 1969 (Suskind and Hertzberg, 1984). Neurologic examination
and nerve-conduction studies did not demonstrate abnormalities compared with
a cohort of unexposed controls; however, the procedure for obtaining controls
did not ensure equivalence. It is unclear whether the four subjects who had acute
neuropathy were included in this effort.
In April 1979, chlorinated dibenzo-p-dioxin contamination was found in a
community in Arkansas that was close to a plant where 2,4,5-T and 2,4-D had
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784 VETERANS AND AGENT ORANGE: UPDATE 2010
been produced since 1957. Fifty-five workers of that plant who had no history of
diabetes or alcohol abuse were identified from the total workforce; these subjects
underwent neurologic examination and nerve-conduction studies (Singer et al.,
1982). Both median motor and sural sensory nerve-conduction studies showed
significantly lower conduction velocity in the workers from the plant than in
control subjects.
Other industrial accidents have also suggested a link between compounds of
interest and early-onset neuropathic symptoms, which persisted in some people.
Jirasek et al. (1974) studied 55 of 80 workers who complained of a variety of
symptoms after chronic exposure to 2,4,5-T at a manufacturing facility in the
Czech Republic; of the 55 workers, 17 had physical examinations suggestive of
neuropathy that was said to have been confirmed with electromyographic abnor-
malities. Follow-up of 44 of the 55 poisoned workers was conducted 10 years
after exposure had ceased; about 30% of them were reported to have continued
neuropathic symptoms (Pazderova-Vejlupkova et al., 1981). More recently, Urban
et al. (2007) evaluated the long-term sequelae of subjects who developed neu -
ropathy after the original exposure. Subjects had increased serum TCDD concen-
trations more than 30 years after exposure, and evidence of continued neuropathy
was noted in 9 of 15 subjects who were available for study.
Acute neuropathic symptoms were reported after the Seveso accident, and
persistent signs were noted. Gilioli et al. (1979) evaluated 35 subjects who had
been exposed during the accident and noted abnormalities in a variety of neu -
rophysiologic measures compared with age-matched controls 2 years after the
exposure. However, it is unclear how the exposed subjects were selected for
study. In a more complete survey, Boeri et al. (1978) studied 470 subjects from
two exposure zones about a year after the accident and found a higher incidence
of neurophysiologic abnormalities than in unexposed controls; the residents of
the zone of greater exposure were more severely affected than those of the less
exposed zone. The same group (Filippini et al., 1981) found increased prevalence
of peripheral neuropathy in residents who had indicators of exposure compared
with those who did not (RR = 2.6, 95% CI 1.0–7.2, for those with choracne; RR
= 3.6, 95% CI 1.3–10.2, for those with increased hepatic enzymes) when they
were evaluated 21 months after the accident. Improvement may have occurred
since the accident. Assennato et al. (1989a,b) studied 193 exposed residents of
the area 9 years after the accident and did not find neurophysiologic abnormali -
ties. However, the number of residents in the group who originally complained of
neuropathic symptoms was not discussed. Similiarly, 6 years after the accident,
Barbieri et al. (1988) examined 153 residents who had developed chloracne.
World Health Organization critieria for neuropathy were not fulfilled for any
subjects, but there was a statistically significant increase in neurophysiologic
abnormalities compared with those in unexposed age-matched controls.
There have been a number of case reports of exposure-associated early-onset
neuropathy. Goldstein et al. (1959) reported the cases of three patients seen at the
Mayo Clinic who had acute weakness and sensory loss demonstrated to be due to
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APPENDIX B
peripheral neuropathy; symptoms occurred within hours of an exposure to 2,4-D
that included sufficient skin contact for clothes and skin to be wet. All three pa -
tients recovered incompletely: in one of the patients, a cerebrospinal fluid (CSF)
examination was normal except for minimally increased protein. Todd (1962)
reported another case of neuropathy that occurred about 4 days after 2,4-D expo -
sure, again in sufficient quantities to cause large areas of skin to be wet from the
herbicide. Clinical examination demonstrated a sensory motor polyneuropathy;
CSF examination showed slightly increased protein but was otherwise normal.
The patient recovered substantially but not completely over 2 years. Finally,
Berkley and Magee (1963) reported a case of a 39-year-old man who had symp -
toms of acute neuropathy that progressed to inability to walk starting 4 days after
2,4-D exposure; CSF analysis was completely normal, including normal protein
concentrations, and he recovered nearly completely over the course of 8 months.
Case reports do not provide conclusive evidence of causal relationships, but
the cases discussed above showed a close temporal relationship between high
exposure to 2,4-D and neuropathy. The most likely non–toxicant-related acute
neuropathy is Guillain-Barré syndrome; however, this syndrome is associated
with characteristic findings on clinical neurophysiologic examination and highly
increased protein in CSF. In the three cases above that had CSF evaluation,
protein concentrations were either normal or increased to a minimal extent not
consistent with Guillain-Barré syndrome. In addition, patients who had clinical
neurophysiologic studies also showed abnormalities not consistent with Guillain-
Barré. Thus, it seems likely that the cases represent the results of 2,4-D exposure.
Biologic Plausibility
Neuronal cell cultures treated with 2,4-D showed decreased neurite extension
associated with intracellular changes, including a decrease in microtubules, in -
hibition of the polymerization of tubulin, disorganization of the Golgi apparatus,
and inhibition of ganglioside synthesis (Rosso et al., 2000a,b). Those mechanisms
are important for maintaining synaptic connections between nerve cells and
supporting the mechanisms involved in axon regeneration during recovery from
peripheral neuropathy. Grahmann et al. (1993) and Grehl et al. (1993) reported
observations of electrophysiologic and pathologic abnormalities, respectively, in
the peripheral nerves of rats treated with TCDD. When the animals were sacri -
ficed 8 months after exposure, there were pathologic evidence of axonal nerve
damage and histologic findings typical of toxicant-induced injury. Those results
constitute evidence of the biologic plausibility of an association between expo -
sure to the chemicals of interest and peripheral neuropathy.
Conclusions
On the basis of studies of health effects after industrial accidents and the
well-documented cases reported above, VAO committees since that responsible
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786 VETERANS AND AGENT ORANGE: UPDATE 2010
for Update 1996 have concluded that there is limited or suggestive evidence of
an association between exposure to the chemicals of interest and early-onset
peripheral neuropathy. Inasmuch as new data on this subject, especially with
regard to Vietnam veterans, are unlikely to emerge, the present committee reaf -
firms that finding.
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