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EPA/600/AP-92/001g
September 1992
Workshop Review Draft
Chapter 7. Epidemiology/Human Data
Health Assessment for
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
and Related Compounds
NOTICE
THIS DOCUMENT IS A PRELIMINARY DRAFT. It has not been formally released by the U S
Environmental Protection Agency and should not at this stage be construed to represent Agency
policy. It is being circulated for comment on its technical accuracy and policy implications
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, D.C.
Printed on Recycled Paper
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DISCLAIMER
This document is a draft for review purposes only and does not constitute Agency policy.
Mention of trade names or commercial products does not constitute endorsement or recommendation
for use.
Please note that this chapter is a preliminary draft and as such represents work
in progress. The chapter is intended to be the basis for review and discussion at
a peer-review workshop. It will be revised subsequent to the workshop as
suggestions and contributions from the scientific community are incorporated.
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CONTENTS
Tables v
List of Abbreviation vii
Authors and Contributors xjj
CANCER EFFECTS , 1.1
Introduction 7_j
Scope f y.j
Previous EPA Reviews ] 7_4
Review Methods 7.4
Follow-Up Studies of Chemical Manufacturing and
Processing Workers 7_7
United States 7_7
Germany ' 7_jQ
Ten-Country Study by International Agency for •••••••
Research on Cancer 7-13
Other Studies 7_15
Summary 7_jg
Case-Control Studies in General Populations y.jg
Sweden . •. _ 7_jo
United States 7_23
New Zealand 7 26
Italy--;:/- •'.'•'.''.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'/.'.'.'.'.'.'.'.'.'.'.'.'. 7-30
Summary _ , , 7_31
Studies of Pulp ard Paper MiU Workers 7_32
Other Studies — 7_32
VietnafftVeterans 7_34
Residents of Seveso, Italy '....- 7.35
Rice Oil Poisonings in Taiwan and Japan—
Compounds Structurally Related to Dioxin 7.37
Conclusions ~_. . 7_39
References | 7_43
HEALTH EFFECTS WER THAN CANCER 7.68
Introduction , 7 &Q
I /-Do
HI
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CONTENTS (continued)
Description of Major Studies 7-68
NIOSH Study 7-69
US Air Force Ranch Hand Study 7-70
Dermal Effects • 7-72
Gastrointestinal Effects 7-74
Liver Size • . • • 7-74
Enzyme Levels • • • 7-74
Porphyrin Metabolism I 7-77
Lipid Metabolism 7-80
Other Gastrointestinal Disorders ; 7-82
Endocrine and Other Metabolic Effects 7-83
Immunologic Effects • 7-84
Neurologic Effects • • - • 7-86
Peripheral Nervous System . 7-86
Respiratory and Cardiovascular Effects 7-90
Respiratory Effects • 7-90
Cardiovascular Effects 7-91
Renal Effects • • 7-92
Reproductive Effects . . . 7-93
Mortality From Causes Other Than Cancer 7-94
Overall Summary of Human Health Effects 7-94
References 7-96
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LIST OF TABLES
CANCER EFFECTS :
1 Relative risks of selected cancers in a study of chemical manufacturing workers
exposed to TCDD in the United States, by exposure, duration, and latency .......... 7-53
2 Relative risks of lung cancer in a sub-cohort of chemical manufacturing workers
exposed to TCDD in the United States for at least one year and with at least 20 years
latency, adjusted for alternative hypotheses about its smoking distribution 7-54
3 Relative risks of all cancer combined in a study of chemical manufacturing workers
exposed to TCDD in Germany, by duration and category of exposure 7.55
4 Relative risks of selected cancers in a study of chemical manufacturing workers
exposed to TCDD in Germany, by median blood TCDD level and latency 7-56
5 Summary of results for selected cancers from follow-up studies of chemical
manufacturing and processing workers exposed to TCDD .'. 7.57
6 Relative risks of soft-tissue sarcomas and malignant lymphomas in relation to phenoxy
acid and chlorophenol exposures in five case-control studies in Sweden 7-58
6B Mantel-Haenszel odds ratios for soft-tissue sarcoma among persons exposed to all
dioxins, TCDD, and dioxins other than TCDD in four case-control studies involving
434 cases and 948 controls 7.59
7 Relative risks of malignant lymphoma and soft-tissue sarcomas in relation to phenoxy
acid and chlorophenol exposures in three case-control studies in Sweden, restricted to
persons who worked in the occupational categories in which these exposures
predominantly occur 7_gQ
8 Relative risks of soft-tisue sarcomas, non-Hodgkin's disease in relation to phenoxy
acid and chlorophenol exposures in two case-control studies in southern Sweden 7-61
9 Relative risks of non-Hodgkin's lymphomas in relation to farm use of 2,4,5-T in case-
control studies in Kansas, eastern Nebraska, Iowa, and Minnesota .../....: 7-62
10 Relative risks of solf-tissue sarcomas and non-Hogkin's lymphomas in relation to
phenoxyacetic acid and chlorophenol exposure in a case-control study in westerm
Washington State, 1981-1984 7.53
11 Relative risks of soft-tissue sarcomas and non-Hodgins lymphomas in relation to
potential exposure to phenoxy acids and chlprophenols in case-control studies in New
Zealand
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TABLES (continued)
12
13
14
Relative risks of soft-tissue sarcomas in relation to phenoxy acid exposure in a case-
control study in northern Italy, 1981-1983
Relative risks for selected cancers from follow-up studies of paper and pulp workers
Relative risks for selected cancers among adults exposed to TCDD in Seveso, Italy .
. 7-65
. 7-66
. 7-67
HEALTH EFFECTS OTHER THAN CANCER
1 Summary of health effects in chemical workers exposed to 2,3,7,8-TCDD-
contaminated materials 7-105
2 Summary of health effects among residents of Seveso, Italy, and Missouri, USA 7-110
3 Summary of health effects among U.S. Air Force ranch hand personnel . .... 7-112
4 Reproductive effects of exposure to chemicals contaminated with 2,3,7,8-
tetrachlorodibenzo-p-dioxin 7-113
5 Studies investigations of their relationship between 2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD) exposure and nonmalignant causes of death 7-114
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ACTH
Ah
AHH
ALT
AST
BDD
BDF
BCF
BGG
bw
cAMP
CDD
cDNA
CDF
CNS
CTL
DCDD
DHT
DMBA
DMSO
DNA
DRE
LIST OF ABBREVIATIONS
Adrenocorticotrophic honnone
Aryl hydrocarbon
Aryl hydrocarbon hydroxylase
L-alanine aminotransferase
L-asparate aminotransferase
Brominated dibenzo-p-dioxin
Brominated dibenzofuran
Bioconcentration factor
Bovine gamma globulin
Body weight
Cyclic 3,5-adenosine monophdsphate
Chlorinated dibenzo-p-dioxin
Complementary DNA
Chlorinated dibenzofuran
Central nervous system
Cytotoxic T-lymphocyte
2,7-Dichlorodibenzo-p-dioxin
5a-Dihydrotestosterone
Dimethylbenzanthracene
Dimethyl sulfoxide
Deoxyribonucleic acid
Dioxin-responsive enhancers
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LIST OF ABBREVIATIONS
DTG
DTK
ECOD
EOF
EGFR
ER
EROD
EOF
FSH
GC-ECD
GC/MS
GOT
GnRH
GST
HVH
HAH
HCDD
HDL
HxCB
HpCDD
Delayed type hypersensitivity
Delayed-type hypersensitivity
Dose effective for 50% of recipients
7-Ethoxycoumarin-O-deethylase
Epidermal growth factor
Epidermal growth factor receptor
Estrogen receptor
7-Ethoxyresurofin 0-deethylase
Enzyme altered foci
Follicle-stimulating hormone
Gas chromatograph-electron capture detection
Gas chromatograph/mass spectrometer
Gamma glutamyl transpeptidase
Gonadotropin-releasing hormone
Glutatnione-S-transferase
Graft versus host
Halogenated aromatic hydrocarbons
Hexachlorodibenzo-p-dioxin
High density lipoprotein
Hexachlorobiphenyl
Heptachlorinated dibenzo-p-dioxin
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HpCDF
HPLC
HRGC/HRMS
HxCDD
HxCDF
LIST OF ABBREVIATIONS (cont.)
Heptachlorinated dibenzofuran
High perfonnance liquid chromatography
High resolution gas chromatography/high resolution mass spectrometry
Hexachlorinated dibenzo-p-dioxin
Hexachlorinated dibenzofuran
I-TEF
LH
LDL
LPL .
LOAEL
LOEL
MCDF
MFO
mRNA
MNNG
NADP
NADPH
NK
NOAEL
NOEL
International TCDD-toxic-equivalency
Dose lethal to 50% of recipients (and all other subscripter dose levels)
Luteinizing hormone
Low density liproprotein
Lipoprotein lipase activity
Lowest-observable-adverse-effect level
Lowest-observed-effect level
6-Methyl- 1 ,3,8-trichlorodibenzofuran
Mixed function oxidase
Messenger RNA
//-methyl-//-nitrosoguanidine
Nicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate (reduced form)
Natural killer
No-observable-adverse-effect level
No-observed-effect level
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OCDD
OCDF
PAH
PB-Pk
PCB
OVX
PBL
PCQ
PeCDD
PeCDF
PEPCK
PGT
PHA
PWM
ppm
ppq
ppt
RNA
SAR
SCOT
SGPT
SRBC
LIST OF ABBREVIATIONS (cont.)
Octachlorodibenzo-p-dioxin
Octachlorodibenzofuran
Polyaromatic hydrocarbon
Physiologically based phamiacokinetic
Polychlorinated biphenyl
Ovariectomized
Peripheral blood lymphocytes
Quaterphenyl
Pentachlorinated dibenzo-p-dioxin
Pentachlorinated dibenzo-p-dioxin
Phosphopenol pyruvate carboxykinase
Placental glutathione transferase
Phytohemagglutinin
Pokeweed mitogen
Parts per million
Parts per trillion
Ribonucleic acid
Structure-activity relationships
Serum glutamic oxaloacetic transaminase
Serum glutamic pyruvic transaminase
Sheep erythrocytes (red blood cells)
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LIST OF ABBREVIATIONS (cont.)
TCAOB
TCB
TCDD
TEF
TGF
tPA
TNF
TNP-LPS
TSH
TTR
UDPGT
URO-D
VLDL
v/v
w/w
Half-time
Tetrachloroazoxybenzene
Tetrachlorobiphenyl
Tetrachlorodibenzo-p-dioxin
Toxic equivalency factors
Thyroid growth factor
Tissue plasminogen activator
Tumor necrosis factor
lipopolysaccharide
Thyroid stimulating hormone
Transthyretrin
UDP-glucuronosyltransferases
Uroporphyrinogen decarboxylase
Very low density lipoprotein
Volume per volume
Weight by weight
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AUTHORS AND CONTRIBUTORS
The Office of Health and Environmental Assessment (OHEA) within the Office of Research
and Development was responsible for the preparation of this chapter. The chapter was prepared
through Syracuse Research Corporation under EPA Contract No. 68-CO-0043, Task 20, with Carol
Haynes, Environmental Criteria and Assessment Office in Cincinnati, OH, serving as Project Officer.
This chapter was prepared in two different sections. The primary author of the cancer effects
section is Charles Poole, with David Bayliss and Steven Bayard of EPA contributing sections and
analyses. David Bayliss, the EPA chapter manager is responsible for the overall content and
conclusions of this section. The author of the section on noncancer health effects is Marie Sweeney of
the National Institute of Occupational Safety and Health, Cincinnati, OH.
EPA CHAPTER MANAGER
David Bayliss
Office of Research and Development
Office of Health and Environmental Assessment
Washington, D.C.
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CHAPTER 7. EPIDEMIOLOGY/HUMAN DATA
CANCER EFFECTS
INTRODUCTION
While animal bioassay data provide substantial presumptive evidence of the human
carcmogenicity of TCDD (Chapter 6), actual validation must come from human studies.
Based on the animal evidence, expected target organs include liver, thyroid, lung, skin and
soft tissues. Based on both animal data and mechanistic considerations cancers associated
with the female reproductive system might be reduced, while lung cancer might be increased
more in males than in females. This chapter reports on the cancer epidemiology evidence of
TCDD and its congeners.
This review and analysis of the epidemiologic literature on dioxins and cancer begins
by defining the scope of chemical exposures, cancers, and research reports to be considered.
Then, following a brief summary of previous EPA assessments of epidemiologic literature, a
description is given of the methods used in the present review. The original research reports
are then discussed in four groups: 1) follow-up studies of chemical manufacturing and
processing workers, 2) case-control studies in general populations, 3) studies of pulp and
paper mill workers, and 4) other studies (including studies of pesticide applicators, Vietnam
veterans with potential exposure to Agent Orange, residents of Seveso, Italy, exposed to
TCDD during an accidentaLexplosion, and victims of contaminated rice oil poisonings).
Because the discussions of the first two groups of studies are relatively lengthy, brief
summaries are given at the end of each of those sections. Conclusions are drawn following
all the groups.
SCOPE
Epidemiologic studies of cancer among persons exposed to 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD) and other polychlorinated dibenzodioxins (PCDDs) and dibenzofurans
(PCDFs) are included in this review. Primary emphasis is placed on studies with exposures
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to TCDD itself, occurring primarily in the manufacture and use of 2,4,5-trichlorophenol,
hexacholorophene and the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Because
exposures to 2,4,5-T and 2,4-dichloroacetic acid (2,4-D) often occur among the same groups
who manufacture and use these herbicides, some studies of groups exposed to only 2,4-D are
also included. Exposure to lower-chlorinated PCDDs (dichlorinated and trichlorinated
isomers) may occur in the manufacture and use of the 2,4-D. Also included are studies of
groups exposed to higher-chlorinated PCDDs (i.e., the hexachlorinated, heptachlorinated and
octachlorinated isomers), occurring primarily in the manufacture and use of pentachlorophenol
and in the paper and pulp industries. .
A major weakness in nearly all of these studies is the lack of good exposure
information. Most studies rely solely on interviews and questionnaires of work history to
ascertain exposure surrogates. There is little, if any, verification of actual internal exposure to
these compounds. Some studies use chloracne as a surrogate for exposure to TCDD. Three
of the recent cohort studies of production workers [8, 17, 18] do provide estimates of TCDD
exposure in cohort samples via serum blood levels taken decades after cessation of exposure.
These can be used to determine possible dose-response trends and to extrapolate to low
exposures (see Chapter 8). Measures of exposure will be discussed by individual study.
At the time of EPA's last review in 1988, evidence of human carcinogenicity of
TCDD and the phenoxy herbicides focused on soft-tissue sarcomas and malignant lymphomas.
Consequently, this report will update and analyze the evidence pertaining to these cancers.
The case control studies reviewed for EPA's last analysis generally considered herbicide
applicators with potential exposures to both 2,4-D and 2,4,5-T. Recent case control studies of
U.S. farmer groups in which exposure to 2,4-D and 2,4,5-T (38, 39, 40) can be separated
provide a validation mechanism to separate potential effects of these herbicides and, possibly,
their different PCDD contaminants. Thus, these and other recent studies [23, 24, 42] will be
reviewed and compared with those discussed in EPA's earlier reports.
Four recent cohort mortality studies [8, 17, 18, 94] totaling over 23,000 workers
potentially exposed to TCDD and/or phenoxy herbicides/chlorophenols provide a new
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important database for analyzing cancer effects and these will be reviewed first. The first
three of these, and especially the large U.S. study of Fingerhut et al [8] are considered to be
the most important new studies in the field of TCDD cancer epidemiology, because of their
attention to cohort selection and to TCDD exposures or exposure surrogates (chloracne). The
fourth study, while having the largest cohort, has less information on the TCDD exposed
subcohort and no information which would allow a quantitative estimate of exposure. Two
other studies of phenoxy acid manufacturers are included [19, 20], but analysis here is limited
due to the low, if any, expected exposure to TCDD.
Three recent cohort studies of workers in the pulp and paper mill industry are included
[53-55] because of potential for worker exposure to higher-chlorinated PCDDs. However,
none of these studies provide any additional information about which PCDD exposures were
likely, and these studies are not given much weight.
Studies of Vietnam veterans potentially exposed to TCDD in Agent Orange are
reviewed briefly, with only one [88] judged to have sufficient information on potential TCDD
exposure to be useful for analysis. Also, the recent studies of the Seveso, Italy residents are
discussed, [89-91]; these studies provide good exposure data, but the cancer response analysis
is limited due to inadequate follow-up time.
Finally, the studies of the rice oil poisonings of residents in Taiwan and Japan with
PCB and PCDF contaminants are reviewed. Even though these poisoned oils did not contain
TCDD, they did contain many TCDD-like congeners currently considered by EPA to have
carcinogenic potential which can be compared to that of TCDD.
Only follow-up and case-control studies are considered in this review. Case reports,
other clinical observations, and prevalence surveys are excluded. The review is restricted to
studies that have been published in full and that are available in the open scientific literature.
Prepublication reports and studies published only in abbreviated form (as well as abstracts or
letters to editors) are included, only where they supplement the published articles. These
restrictions limit the review to studies that have received at least a minimum of peer review
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and that have been described fully enough to permit a thorough assessment of materials,
methods and results.
PREVIOUS EPA REVIEWS
In "Health Assessment Document for Polychlorinated Dibenzo-p-Dioxins," dated
September 1985 [1], the majority of the epidemiology studies pertained to groups of herbicide
applicators with potential exposure to phenoxy acids and/or chlorophenols. In that report the
analysis emphasized case-control studies of soft tissue sarcomas (STS) and non-Hodgkins'
lymphoma (NHL). That report concluded that the epidemiologic research available at that
time provided "limited evidence for the carcinogenicity of phenoxy acids and/or chlorophenols
in humans. However, with respect to the dioxin impurities contained therein, the evidence for
the human carcinogenicity for 2,3,7,8-TCDD based on the epidemiologic studies is only
suggestive because of the difficulty of evaluating the risk of 2,3,7,8-TCDD exposure in the
presence of the confounding effects of phenoxy acids and/or chlorophenols." In its next
report, the review draft dated June, 1988 of "A Cancer Risk-Specific Dose Estimate for
2,3,7,8-TCDD" [2], the focus was essentially the same and the EPA concluded that "the
human evidence supporting an association between exposure to 2,3,7,8-TCDD and cancer is
considered inadequate."
REVIEW METHODS
This review will follow the spirit of the EPA "Risk Assessment Guidelines of 1986"
[3] by considering alternative explanations for results observed in epidemiologic studies.
These explanations fall into the general categories of causality, chance, bias and confounding.
The basic approach is akin to a process of elimination, by which one attempts to determine
the direction and to quantify the magnitude of the influence that chance, bias and confounding
may have had on the results of each study. Wherever possible the results of all studies will
be reported in units of relative risk estimates, and 95% confidence limits.
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Most biases in epidemiologic studies can be placed into one of two categories: biases
of classification and biases of selection. Classification biases can result from inaccurate
ascertainment of exposure, disease or confounders. Selection biases can result from non-
representative sampling of populations, as in the selection of controls in case-control studies,
or from incomplete participation by study subjects. Any bias gains tenability as an
explanation for an observed result if empirical evidence can be adduced to buttress the mere
suggestion that the bias might have occurred. Only those biases considered to be potentially
important will be addressed explicitly in this review.
Confounding, sometimes considered a type of bias, is a tenable explanation for an
association between an exposure and a disease if the hypothetical confounder can be named
and if a good case can be made that it is a cause of the disease, that it was associated with
the exposure in the study population, and that it was not adequately controlled in the study
design or data analysis. This review will explicitly mention only those potential confounders
that meet all of these criteria.
As stressed in previous EPA reviews [1,2], concomitant exposures present a special
problem of potential confounding in the literature on TCDD and related chemicals. As a
noteworthy example, an association between 2,4,5-T exposure and a given cancer, if causal,
could be due to 2,4,5-T itself, to TCDD, or to some other contaminant. The problem
multiplies when it is recognized that, historically, many phenoxy acid herbicide preparations
were mixtures of 2,4,5-T and 2,4-D and that many persons who manufactured, processed and
used these preparations were exposed to other chemicals as well. Nevertheless, it may be
possible by examining studies of persons exposed to different combinations of chemicals to
identify "threads" of commonality and differences in the results, especially when specific
cancers are considered separately.
"Publication bias," sometimes considered a form of selection bias, is the tendency for
the results of a study to influence whether or not it is published. The direction and
magnitude of publication bias is difficult, if not impossible, to quantify. It is expected to be a
much greater problem in literature reviews and in studies relying on existing records than in
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original research in which substantial resources are devoted to collection of data of relatively
high quality. The level of effort required for such studies creates a strong incentive to
publish the results.
Strength of association, as measured by the magnitude of the estimated relative risk, is
an important feature of a study's results. The stronger the association, the stronger a bias or
confounding factor would have to be to explain it. Because questions of bias and
confounding are study-specific, no defensible criteria can be set up in advance to place
relative risk values into categories of strength of association.
Trends in increased risk by degree of exposure and by time since first exposure
("latency") are also important. Different hypothetical causal mechanisms might predict
different exposure-response and latency patterns. Hypotheses of steadily increasing effect
with increasing exposure (i.e., monotonic exposure-response functions) and hypotheses of
effects early in the carcinogenic process (e.g., for factors that operate at the initiation stage)
predict that increases in risk will be greatest among persons with relatively high degrees of
exposure and after relatively long latency periods. Other hypotheses would predict other
patterns.
Replication of results is important in all scientific research. Not only does it provide a
safeguard against the fluke observation, but it also serves as a test of methodologic
hypotheses. It is valuable for results to be replicated with different methods in different
populations and by different investigators than for these features to be held constant across
studies in so-called "pure" replication.
The statistical aggregation of results from different studies ("meta-analysis") has
become a popular feature of epidemiologic literature reviews. In this review, results from
separate studies are aggregated only when all key methodologic features and results are
reasonably similar. The method of aggregation used here is to take the ratio of the sume of
the cause-specific observed deaths to the sum of the cause-specific expected deaths for the
individual studies. Because investigators recognize the value of varying their methods to test
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methodologic hypotheses, and because results often differ appreciably, aggregation of results
is not often indicated and is done here with caution.
FOLLOW-UP STUDIES OF CHEMICAL MANUFACTURING AND PROCESSING
WORKERS
United States
Fingerhut and colleagues [7,8] reported a study of 5,172 persons who had worked at 12 plants
in the United States in the production of chemicals contaminated with TCDD. Five thousand
of the cohort members (97 percent) were identified in company records as having been
"assigned to a production or maintenance job in a process involving TCDD contamination"
[8]. The remaining 172 cohort members v/ere "identified in a previously published study on
the basis of exposure to TCDD" [8]. This cohort subsumed, and thereby supplanted,
company-specific cohorts from Dow Chemical USA [9, 95] and the Monsanto Company
[10,11] that had been the subject of previous reports. Follow-up began in 1940 or on the date
of the "first systematically documented assignment to a process involving TCDD
contamination" [8], whichever was later, and closed at the end of 1987. Comparisons were
made with the United States population.
The authors stated that approximately 13% of the cohort of 5,172 workers had records
of chloracne. The presence of chloracne in a group of people is an indicator of relatively
intense exposure to TCDD, it can be caused by higher-chlorinated PCDDs as well [13]. It is
a highly sensitive indicator of exposure because it virtually never occurs among unexposed
persons. It is a non-specific indicator, however, because many highly exposed persons do not
develop it [12,14].
Although all members of the cohort had specific assignments to TCDD exposure areas
in common, exposures to multiple chemicals are the rule rather than the exception in the
chemical industry. At one plant, for instance, considerable overlap existed among persons
exposed involved in the production of chlorophenols, 2,4,5-T and 2,4-D [9,15], and who were
thus exposed to TCDD and higher-chlorinated and lower-chlorinated PCDDs. Presumably,
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many persons throughout the cohort had contact with substantial numbers of other chemicals.
For none of the plant-specific cohorts was a comprehensive survey of chemical exposures
conducted.
Special attention was paid to results for the 3,036 workers who were followed at least
20 years after first exposure. This group was again diveded into those with less than 1 year
(N=l,516) and those with more than 1 year (1,520) exposure (referred to below as the long
duration/latency sub-cohort). One year was chosen as the criterion for duration of exposure
because an analysis of 253 workers from two plants showed that every worker with one or
more years of exposure had a lipid-adjusted serum TCDD level greater than the mean value
in a comparison group of unexposed workers (seven ppt) [7]. The researchers described a
plan to replace this duration-based exposure scale by using "a dioxin exposure matrix
constructed from historic process descriptions, analytic measurements of TCDD and industrial
hygiene data...to develop the relative ranking of workers exposed to TCDD" [7].
The cohort as a whole experienced an estimated 15 percent (95% C.I., 1.0-1.3)
elevation of mortality from all cancers combined, with a 50 percent elevation (95% C.I., 1.2-
1.8) among those in the long duration/latency sub-cohort (Table 1). An excess of deaths from
cancers of connective and soft tissues (STS) was apparent in the total cohort (RR = 3.4, C.I.,
0.9-8.6), and in the long duration/latency sub-cohort (RR = 9.2, C.I., 1.9-27.0), but these
results were based on only four deaths and three deaths respectively, from two different
plants. A 40 percent overall elevation in deaths (C.I., 0.7-2.5) from non-Hodgkin's
lymphoma was confined to workers in the total cohort, and was not seen in the long
duration/latency sub-cohort. Results for Hodgkin's disease were highly imprecise, based on
only three deaths (vs. 2.5 expected) in the total cohort. Lung cancer was elevated by 10
percent overall but by 40 percent (C.I., 1.0 - 1.9) in the long duration/latency sub-cohort. A
similar 40 percent excess of stomach cancer (C.I., 0.4 - 3.3) in this sub-cohort was based on
only four deaths; no excess was seen in the total cohort.
The investigators conducted a special study of connective and soft tissue cancers. A
review of all available hospital records and tissue specimens failed to confirm the indications
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of soft-tissue sarcomas on two of the four death certificates that had been assigned to this
cause-of-death category [7], The review also provided evidence that two persons whose
deaths had been assigned to other causes of death had actually had soft-tissue sarcomas.
Because only the exposed cohort's death certificates were subjected to detailed review, the
analytic comparisons with the United States population were required to be based strictly on
death-certificate information. The basic and well-known rule in such situations is that, absent
evidence to the contrary, erroneous information on death certificates must be considered to
have been equally frequent in the two groups being compared. However, even if all extra
information had been used inappropriately to adjust the data for the exposed cohort, the two
apparent "false positives" and the two apparent "false negatives" would have cancelled each
other, leaving the total number of deaths from connective and soft tissue cancers unchanged
at four.
Confounding by cigarette smoking must be considered in interpreting the approximate
40 percent excess of lung cancer deaths in the long duration/latency sub-cohort (Table 1).
For the United States as a whole, the authors [7] computed age-adjusted proportions of 24
percent never smokers, 19 percent former smokers and 57 percent current smokers in 1965
(roughly midway through the follow-up period). The corresponding proportions were 28
percent never smokers, 14 percent former smokers and 59 percent current smokers among the
87 workers from the study of serum TCDD levels who were members of the long
duration/latency sub-cohort as well. Assuming relative risks of lung cancer of 4.7 for former
smokers and 10.9 for current smokers, the authors used a standard technique [16] to adjust the
number of expected lung cancer deaths and found essentially no change in the results.
Furthermore, the authors point out that deaths from other diseases associated with smoking
such as diseases of the heart and circulatory system were either not increased or significantly
decreased, respectively [7]. This lead the authors to conclude that "cancers of the respiratory
tract... may result from exposure to TCDD, although we cannot exclude the possible
contribution of factors such as smoking and to other industrial chemicals" [8].
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One possible explanation for the increase follows from that fact that the comparison of
smoking habits between the United States and the 87 surviving members of the long
duration/latency sub-cohort did not show the well-known tendency for smoking to be more
common among blue-collar workers than in the general population. A possible explanation
for this result is that, because smoking appreciably elevates the overall death rate, fewer and
fewer smokers will remain in a fixed group of persons as time goes by. Thus, the use of the
87 surviving members of the long duration/latency sub-cohort may have substantially
underestimated the proportions of former and current smokers in the sub-cohort as a whole
over the course of mortality follow-up. As shown in Table 2, the actual proportions would
not have to be inordinately high for smoking to have exerted appreciable confounding on the
estimated relative risks of lung cancer. The lack of increased mortality from cardiovascular
diseases in this cohort, however, makes this explanation less likely.
Germany
Manz and colleagues [17] reported a study of 1,583 persons (1183 men and 399
women) employed at a German chemical manufacturing facility that produced 2,4,5-T and its
precursor, 2,4,5-trichlorophenol. In 1954, a chloracne outbreak had occurred in the working
population of the plant, and after that, production of the TCDD contaminant was reduced.
Cohort members worked at least three months from 1952 through 1984. Start of follow-up
was not stated in the report, but presumably began on the date of accumulation of three
months of employment. The follow-up period closed at the end of 1989. The cohort's
mortality experience was compared with that of the West German population and with that of
a cohort of workers at a gas supply company. Because the results did not differ materially
between the analyses, and because limited data on the gas workers forced that comparison to
be based on a subset of the TCDD-exposed cohort, only the results of the comparisons with
West Germany are reported here.
The cohort was post-divided by duration of employment and by a three-category
exposure scale based on TCDD measurements "in nonsystematic samples of precursor
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materials, products, waste, and soil from the grounds of the plant, mainly after the plant had
closed in 1984" [17]. This scale was validated to some extent by adipose tissue TCDD levels
in 48 volunteers (mean = 296 ng/kg in 37 persons from the highest group, 83 ng/kg in 11
persons from the other two groups). Based on these results, the low and intermediate groups
are combined for the present analysis.
For the males, this study with 75 total cancer deaths expected and 24 expected in the
high-exposure subcohort, was considerably smaller than the study by Fingerhut et al. [8],
which had 230 total cancer deaths expected and 78 in its long duration/latency sub-cohort
(Table 1). Manz et al. presented detailed analyses only for all cancers combined. The high
exposure sub-cohort, and especially those with longer employment duration, experienced an
excess of total cancer deaths, (RR = 1.4, C.I., 1.0-2.0 for the high exposure group, and RR =
2.6, C.I., 1.2-4.9 for the high exposed/long duration sub-cohort) (Table 3). The authors
concluded that "the increase in (total) cancer risk of 1.24-1.39 ... cannot be explained
completely by confounding factors, and ... is associated with exposure to TCDD" [17].
For the cohort as a whole, the estimated relative risk of lung cancer was 1.4 (C.I., 1.0-
2.0, 30 observed deaths). Smoking as an explanation for the observed increase in lung cancer
mortality is less likely since a comparison using the gas worker reference actually leads to an
increased RR of 1.7 (C.I., 1.1-2.4). The estimate for stomach cancer was 1.2 (C.I., 0.7-2.1,
12 observed deaths). Three deaths from rion-Hodgkin's lymphomas and no connective and
soft tissue cancer deaths were observed. (The authors described an additional three deaths
from chronic lymphocytic leukemia as non-Hodgkin's lymphoma deaths, but these deaths
would not have been classified as non-Hodgkin's lymphomas in the other studies in this
review.) Expected numbers of deaths from these cancers were not given. Based on the
proportions of expected cancer deaths in the Fingerhut study, one might estimate that
approximately 2.4 non-Hodgkin's lymphoma deaths and 0.4 connective and soft-tissue cancer
deaths would have been expected in this cohort as a whole, and about 0.1 connective and soft
tissue cancer deaths in the high exposure sub-cohort. (The numbers of expected deaths from
lung cancer, stomach cancer or non-Hodgkin's lymphoma in the high exposure sub-cohort
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were not estimated because information is lacking on how many of the observed deaths from
these cancers were in that sub-cohort.)
Of the 399 female cohort members only 7% worked in high exposure departments. In
total, there were 54 deaths and an overall RR = 0.8 (C.I., 0.6-1.0). The RR for all cancers
was 0.9 (C.I., 0.6-1.4), but the RR = 2.2 (C.I., 1.0-4.1) for breast cancer was significantly
increased based on 9 deaths. This is an interesting result in view of an expectation of
reduced mammary cancer based on mechanistic studies and animal bioassays. However, at
this point the data do not provide a sufficient basis for any conclusions. Of all the worker
follow-up studies with TCDD, this is the only one which reports on a cohort of females.
In another investigation in Germany, Zober and colleagues [18] studied persons
employed at a German chemical manufacturing facility where 2,4,5-trichlorophenol was
produced. An uncontrolled decomposition reaction in 1953 and subsequent clean-up activities
had resulted in substantial TCDD exposures. The cohort contained 247 persons who had
worked at the plant from 1953 through 1987, 51 percent of whom had developed chloracne or
erythema (a skin condition suggestive of chloracne), with mortality follow-up covering the
same calendar period. Seventy eight persons had died, RR = 0.95; 23 had died of cancer, RR
= 1.2.
Three sub-cohorts were defined on the basis of procedures by which cohort members
were identified as having potential for varying degrees of exposure. Subcohort Cl contained
69 persons known to be exposed to TCDD during the accident period. Cohorts C2 (84
persons) and C3 (94 persons) contain workers thought to be exposed to lesser amounts of
TCDD. Recent TCDD levels in blood samples from small numbers of persons in each group
suggested that exposures had been higher in Cl (median 24.5 ppt, 11 samples) than in C2
(median 9.5 ppt, 7 samples) or C3 (median 8.4 ppt, 10 samples). Thus, C2 and C3 are
grouped together in the present review. A separate analysis by the authors divides the group
into the 127 persons with chloracne (N = 114) and erythema (N = 13) vs. those 120 persons
with neither. The average serum TCDD levels in the two subcohorts are 50 and 26,
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respectively. The two stratifications provide similar results. Only the first is presented here.
Section 8.4 provides an additional analysis.
This study, with only 20 expected cancer deaths in the total cohort and four expected
cancer deaths in the members of sub-cohort Cl with 20 or more years of latency, is much
smaller than the studies by Fingerhut et al. [8] and Manz et al. [17]. The authors, however,
did provide detailed analyses of data on specific cancers (Table 4). Elevated mortality rates
from lung cancer, stomach cancer and all cancers combined were confined largely to the
members of sub-cohort Cl with long latency. The confidence intervals for the relative risk
estimates are extremely wide, however. No deaths from cancers of connective and soft
tissues or from non-Hodgkin's lymphomas were observed and expected numbers of deaths
from these cancers were not reported. Based on the proportions of all expected cancer deaths
due to these cancers in the study by Fingerhut et al. [8], one might estimate that
approximately and 0.6 non-Hodgkin's lymphoma deaths and 0.1 connective and soft tissue
cancer deaths would have been expected in this cohort as a whole, and about 0.2 non-
Hodgkin's lymphoma deaths and less than 0.1 connective and soft tissue cancer deaths among
the members of sub-cohort Cl with long latency.
Ten Country Study By International Agency for Research on Cancer
An historical cohort study of cancer mortality in 18,390 production workers or
sprayers exposed to chlorophenoxy herbicides and/or chlorophenols was reported on by
Saracci et al [94]. Exposure was reconstructed through questionnaires, factory or spraying
records, and job histories. Workers were classified as exposed (N = 13,482), probably
exposed (N = 416), exposure unknown (N = 416) and non exposed (N = 3,951). The exposed
group contains everyone known to have sprayed chlorophenoxy herbicides and everyone who
had worked in any of certain specified departments at factories producing chlorophenoxy
herbicides. Criterion for duration or level of exposure required for selection was reported for
only three of the ten countries and only four of the twenty cohorts; these ranged from at least
1 month to 1 year. For all the other cohorts the criterion for inclusion was ever employed in
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production or spraying of these herbicides. The cohort contained 1,537 female workers, but
results were not presented separately, except for female breast and genital organ cancers by
phenoxy herbicide exposure. Average follow-up for the cohort was 17 years; 5% of eligible
workers were lost to follow-up. Two of the cohorts comprising over 10,000 workers have
also been reported in separate publications but for different follow-up periods [19, 20]; these
are discussed briefly in this report following the present discussion.
Also included in the analysis was a division of the cohort (by probable vs. unlikely)
by whether or not exposure to TCDD occurred. No duration or level of exposure was
specified as being a division criterion. The "probably exposed" appear to be included because
they either sprayed 2,4,5-T or worked in a factory producing it. Those "unlikely exposed"
appear to be so classified because they worked in different factories. There were 181 cases of
chloracne among workers in the cohort, 128 of whom were from 1 plant of 159, but no
separate analysis is presented. The results are presented below by each of the two divisions
of the total cohort a) phenoxy herbicide (ph) and/or chlorophenols and b) probable TCDD
exposure.
For the cohort division by a) ph and chlorophenols no excess was observed for all-
cause mortality, for all malignant neoplasms, for most common epithelial cancers, or for
lymphomas. The four STS deaths were all in the "exposed" sub-cohort (RR = 2.0; C.I., 0.5-
5.2), and all appeared 10-19 years after first exposure (RR = 6.1; C.I., 1.6-15.5), with the
excess limited to exposed sprayers (RR = 8.8, C.I., 1.8-25.8) based on 3 observed deaths.
Increases were also noted in the exposed group for mortality from thyroid cancer (RR = 3.7,
C.I., 1.0-9.4) based on 4 deaths, cancer of the testis (RR = 2.2; C.I. 0.0-4.6), based on seven
deaths, other endocrine glands (RR = 4.6; C.I. 0.9-13.5) based on 3 deaths, and nose and
nasal cavities (RR = 2.9; C.I., 0.6-8.5) based on 3 deaths. An increase in lung cancer
mortality was limited to the probably exposed group (RR = 2.2; C.I., 1.1-4.0) based on 11
observed deaths. While all these results are interesting, the lack of better exposure
information and the small numbers limit the confidence to make any conclusions.
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The authors provided an additional analysis of STS, including 5 additional cases who
were either alive at the end of follow-up or who had died from another cause. They
concluded that the results suggest that STS in these workers "is compatible with a causal role
for chlorophenoxy herbicides, though not specifically for those probably contaminated with
TCDD."
For the subcohort post stratification b) exposure to TCDD, the authors present only
limited analysis based on 215 and 294 expected total cancer deaths in the "probably" vs.
"unlikely" exposed groups, respectively. There was a slight increase in mortality from all
cancers for the probably vs. the unlikely exposed groups (RR = 1.1; C.I., 1.0-1.2) vs. (RR =
0.9; C.I. 0.8-1.1) but no increase in either STS or NHL based on 4 and 11 total cases,
respectively. There was also an increased mortality for testicular cancer in the probably
exposed group (RR = 3.0 vs 1.6) based on 7 total deaths, and for thyroid cancer (RR = 4.3
'vs. 3.1) based on 4 total deaths. These latter two differences do not appear to be significant
and, while interesting because of TCDD's known effects on these organs, add little to the
information base.
While the Saracci et al is cohort is significantly larger than the other three worker
cohorts [8, 17, 18], the lack of both a clear definition of exposure and uniformity on exposure
classification both between and within plants makes the results difficult to interpret and
lessens the confidence in these conclusions. TCDD tissue levels were available only from a
sample of 9 of the 181 workers with chloracne, and no analysis was presented on these
workers.
Other Studies
Two studies containing portions of the same cohort reported above were reported
elsewhere [19, 20]. Lynge [19] reported a study of cancer incidence among persons
employed in the manufacture of phenoxy herbicides in Denmark. The cohort consisted of
4,459 persons from two plants. One plant contributed 615 cohort members who had worked
in the years 1951-1981. The only phenoxy acids manufactured and packaged at this plant
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were 4-chloro-2-methylphenoxyacetic acid (MCPA) and mecoprop. The other plant
contributed 3,844 cohort members who had worked in the years 1933-1981. At this plant,
MCPA, 2,4-D, and substantially lesser amounts of mecoprop, dichlorprop and 2,4,5-T, were
manufactured and packaged. The investigators were unable to classify cohort members by the
specific types of phenoxy herbicides to which they were exposed.
Coggon and colleagues [20] conducted a study of 5,754 workers at a British plant that
manufactured and formulated MCPA from 1947 until 1982 and operated its own aerial and
tractor-mounted spraying service from 1947 until 1972. The authors stated that other phenoxy
acids were handled "at times" and that, "in comparison with MCPA, 2,4,5-T was handled only
on a small scale."
Exposures to TCDD appear to have been infrequent among members of these two
cohorts, and the researchers did not have information sufficient to identify specifically those
persons who did receive TCDD exposures. Consequently, these studies will not be further
reviewed here.
Summary
The cohorts assembled by Fingerhut et al. [8], Manz et al. [17], and Zober et al. [18]
are important because they contain sizable proportions of persons with substantial TCDD
exposures. These exposures were documented, at least in subsets of the cohorts, by blood
and/or adipose tissue measurements, workplace measurements, and the occurrence of
chloracne. The Saracci et al cohort, while significantly larger, is assembed with nonuniform
exposure criteria for TCDD exposure, leading to less confidence in the results.
The exposures and methods in the three former studies in males were similar enough
to warrant aggregating the results. Within each study, relative risks were estimated by
summing the observed and expected numbers of deaths across categories of age, race and
calendar time, and then dividing the totals to produce relative risk estimates in the form of
standardized mortality ratios. Thus, aggregate relative risks can be obtained simply by
summing the observed and expected numbers of deaths across the studies. Alternatively, the
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aggregate relative risk could have been derived by weighting the individual relative risks from
each study by the inverse of the variance. A separate analysis of the three studies using
estimates of lifetime dose intake is presented in Section 8.4.
As shown in Table 5, the studies by Manz et al. [17] and Zober et al. [18] add little to
the information provided by the study by Fingerhut et al. [8], except to increase the precision
of the relative risk estimates (as indicated by a narrowing of the confidence intervals). Even
when aggregated, however, the estimates for cancers of connective and soft tissues, non-
Hodgkin's lymphoma and stomach cancer are highly imprecise. With this important
limitation, the results suggest little or no increase in the risk of non-Hodgkin's lymphomas.
They also suggest increase risk -- especially among persons with relatively high exposure and
relatively long latency - for connective and soft tissue cancers, for lung cancer, and for all
cancers combined. The only study in females [17] suggests a possible increased risk of breast
cancer, but the results are considered preliminary in view of the small numbers and less
certain exposure.
The estimates of increased risk for lung cancer and for all cancers combined are
considerably more precise (Table 5). The elevations for these cancers also appear to be more
pronounced in the sub-cohorts of relatively high exposure and relatively long latency than in
the total cohorts. Because they come from comparisons between blue-collar workers and
national populations, it is reasonable to suspect that these estimates - especially for lung
cancer -are inflated to some degree by confounding by cigarette smoking, but the limited
analyses presented suggest that the association is real.
The results in males are consistent with results from animal studies to some degree.
In chpater 6 it was shown that in a lifetime TCDD bioassay female rats developed lung
cancer, and in an initian-promotion study ovariectomized rats exposed to TCDD developed
lung tumors, while intact rats similarly exposed did not. Furthermore, the mice in the NCI
study developed fibromas and fibrosarcomos. Also, TCDD affects the immune system and
has been shown to be a tumor promoter in animal liver and skin assays. Either or both of
these actions could lead to increased total cancer. On the other hand, TCDD exposure might
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be expected to result in decreased breast cancer in females based similar observations in rats
and on TCDD's action on down regulation of the estrogen receptor, but this result was not
seen.
CASE-CONTROL STUDIES IN GENERAL POPULATIONS
Sweden
Hardell, Eriksson and colleagues conducted four studies of soft-tissue sarcomas [21-
24] and one study of malignant lymphomas [25] among men living in different parts of
Sweden. In all studies, cases and their matched controls were considered exposed if they
reported phenoxy acid or chlorophenol exposures lasting at least one day and occurring at
least five years before the case's date of diagnosis.
The nature of the phenoxy acid exposures differed across the Swedish study locales.
In northern Sweden, most exposures occurred in the use of 2,4,5-T and 2,4-D in combination
in forestry applications, often by knapsack spraying [21,23,25,26]. Phenoxy acid exposures
not involving 2,4,5-T became progressively more common, on a proportional basis, in the
central and southern regions in which agricultural herbicide uses predominated [22,24].
Whereas exposures not involving 2,4,5-T made up only 22 percent of all phenoxy acid
exposures in the first northern sarcoma study [21,26], they accounted for 27 percent in the
study in central Sweden [24] and 58 percent in the study in southern Sweden [22]. Exposures
defined only as phenoxy acid exposures are therefore less useful as indicators of exposure to
TCDD and related compounds in southern Sweden than in the central and northern parts of
the country. Furthermore, none of these studies provide information dealing with how much
exposure each subject may have had.
The reports contain little information on the specific chlorophenol preparations to
which the cases and controls were exposed. Occasional statements in some of the
manuscripts suggest that most chlorophenol exposures occurred in the sawmill and pulp
industries, that they primarily involved pentachlorophenol and that they seldom involved
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trichlorophenols. Thus, most of the reported chlorophenol exposures entailed exposures to the
higher-chlorinated PCDDs but not to TCDD.
Because exposure prevalences were generally low and, because phenoxy acids and
chlorophenols tend to be used in different occupations, very few persons reported joint
exposures. Thus, it is efficient to control potential confounding in the analysis of data from
these studies by comparing each exposure category (phenoxy acids versus chlorophenols) with
the category composed of all persons who reported no exposure to phenoxy acids or
chlorophenols. Based on this method of analysis, relative risk estimates from all five studies
are presented in Table 6, with the sarcoma studies arranged in order of publication.
The results for 2,4,5-T are the only results pertinent to TCDD exposures. Because of
the the small number of cases and controls reporting 2,4,5-T use in southern Sweden, the
confidence interval for the relative risk estimate from the study in that part of the country
[22] is extremely wide. A separate relative risk estimate for 2,4,5-T could not be computed
from the data in the second northern sarcoma study [23]. The published report, however, did
state that all of the cases and most of the controls exposed to phenoxy acids were exposed to
preparations including 2,4,5-T [23]. The report also gave a relative risk of 3.5 for TCDD
exposure, but no confidence interval or counts of cases and controls was provided.
The studies were conducted in two phases. The lymphoma study [25], the first
northern sarcoma study [21] and the southern sarcoma study [22] were published between
1979 and 1981. The remaining two sarcoma studies [23,24] appeared about a decade later.
The relative risk estimates from these more recent studies are consistently lower than those
from the earlier studies (Table 6). Thus, systematic differences between the two sets of
studies may be an explanation for the heterogeneity of results.
The first set of studies had received a considerable amount of criticism concerning the
methods by which the exposure information had been obtained [26,27]. The basic concern
was the possibility of bias from differential exposure misclassification between cases and
controls (sometimes called "observational bias" or "interviewer and recall bias"), with false-
negative reports of exposure suspected as being more common among the controls and false-
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positive reports more common among the cases. Much of the discussion focused on
telephone interviews that were conducted by research staff who were aware of the purpose of
the study and of the case or control status of the respondents. These interviews were
conducted with selected participants to confirm reported exposures and to resolve
uncertainties on postal questionnaires, which were the primary sources of exposure
information. As the criticisms of these procedures have echoed through the years [4,29], no
quantitative analysis has been made of the degree of bias that would have been required to
produce the very strong associations reported in the first three studies (Table 6). Of greater
importance, analyses by Hardell based solely on the questionnaire information [30] have been
largely overlooked. These analyses produced relative risk estimates very similar to those
obtained when the information from the supplemental interviews was used.
Hardell also went so far as to enroll a series of colon cancer patients [30] as a sort of
"positive control" group. In contrast to soft-tissue sarcomas and malignant lymphomas, colon
cancer turned out not to be associated strongly with phenoxy acid or chlorophenol exposures.
Hardell and Eriksson made a similar finding in one of the newer studies [23], when they
included a control group consisting of a variety of cancers along with a set of general-
population controls.
Despite HardeU's conclusion that "the previously reported associations...cannot to any
essential degree be explained by observational bias in the studies" [30], he and his colleagues
imposed procedures designed to reduce the potential for such bias in their subsequent studies
[24,25]. When lower relative risk estimates were produced (Table 6), the researchers
suggested that one explanation might have been the improved methods of exposure
assessment
The investigators suggested that another explanation for the reduced relative risk
estimate for phenoxy acids and soft-tissue sarcomas in the study in central Sweden (Table 6)
"could be the decade in which exposure occurred" [24], with the implication that exposures
were higher in earlier decades. They supported this suggestion with an analysis in which only
those phenoxy acid exposures occurring in the 1950s were considered. This analysis yielded
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a higher relative risk estimate of 2.3 (95 percent confidence interval 1.0 - 5.4).
Unfortunately, no basis of comparison exists because analyses by calendar time of exposure
were not conducted in any of the other studies.
As an alternative explanation for the lack of an elevated relative risk estimate in
connection with chlorophenols in the second northern sarcoma study (Table 6), the authors
offered "random variation" due to a low number of exposed subjects [23]. This explanation is
not persuasive in light of the fact that the prevalence of chlorophenol exposures among the
controls in that study (10.9 percent) was several times higher than in the earlier northern
sarcoma study (2.9 percent) [21], and virtually identical to the prevalence in the lymphoma
study (10.4 percent) [25]. The phenoxy acid exposure prevalences were highly uniform in all
three northern studies: 7.2 percent in the lymphoma study [25], 6.8 percent in the first
sarcoma study [21], and 7.1 percent in the second sarcoma study [23]. Thus, the only outlier
was the chlorophenol exposure prevalence among the controls in the first northern sarcoma
study [21], and that prevalence seems to have been aberrantly low.
For three of the studies by Hardell and colleagues, relative risk estimates can be
computed restricting the data to persons who had worked in agriculture and the other
occupational categories in which the exposures of interest tend predominantly to occur (Table
7). For the lymphoma study [25] and the sarcoma study in southern Sweden [22], the results
for exposure to phenoxy acids, chlorophenols or both in the restricted analyses are virtually
identical to those obtained with the data for all subjects (Table 6). For the sarcoma study in
central Sweden [24], however, the relative risk for phenoxy acids was higher (2.3) within the
special occupational categories than among all subjects.
These analyses are important because many of the mechanisms by which biases might
occur would be related to occupation. For instance, biases in case identification, control
selection or non-participation that might be related to occupational status (e.g., by its link to
socioeconomic status) would not be expected to be as great in analyses conducted within the
occupational categories as in analyses of .the overall data. The potential for confounding by
occupational exposures encountered in the same lines of work would also be reduced in the
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occupationally restricted analyses. Several researchers and reviewers [31-33] have noted
reports of farmers being at increased risk of malignant lymphomas and other cancers, and
have mentioned a wide range of potentially responsible exposures, "including pesticides,
solvents, oils and fuels, dusts, paints, welding fumes, zoonotic viruses, microbes, and fungi"
[33]. (Studies of farmers and other agricultural workers per se are not included in the present
review because mere membership in these occupational categories is insufficient as an
indicator of exposure to such substances as 2,4,5-T or chlorophenols.)
In the original reports, occasional attempts to assess exposure-response trends
produced mixed results. In general, the reported exposure periods were short in all of the
studies. In the first northern sarcoma study, for instance, 93 percent of all reported phenoxy
acid exposures lasted one year or less, 74 percent lasted six months or less, and 33 percent
lasted 30 days or less [21,26]. Reported exposures in southern Sweden were even briefer,
with 53 percent lasting 30 days or less [22].
Hardell et al. recently aggregated the four soft-tissue sarcoma studies in a re-analysis
examining exposures to herbicides contaminated with TCDD and other dioxins [34].
Increasing trends in risk with duration of exposure (<1 year and >1 year) and "latency" (5-19
years and ^:20 years since first exposure) were numerically impressive, being based on the
totals of 434 cases and 948 controls from all the studies (Table 6b). The problem of
concomitant exposures was not solved in these analyses, however, and an analysis of the
aggregated data obscured the pronounced heterogeneity of results among the individual
studies (Table 6).
Regardless of the exposure definition, considerable heterogeneity exists among the
relative risk estimates from the four soft-tissue sarcoma studies (Table 6). (Tests of
homogeneity yield two-tailed p-values of 0.002 for phenoxy acids, chlorophenols or both;
0.02 for phenoxy acids; 0.03 for 2,4,5-T; and 0.01 for chlorophenols.) In this circumstance,
aggregation of results across studies is not indicated and, instead, a search should be made for
explanations for the heterogeneity.
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Two additional studies of malignant lymphomas and one study of soft-tissue sarcomas
were conducted by independent research teams in southern Sweden. Olsson and Brandt's
study [35] consisted of 167 men diagnosed with non-Hodgkin's lymphoma in the years 1978-
1981 and 140 controls. Men who reported handling phenoxy acids or chlorophenols for at
least one day were considered exposed. However, the main focus of the study was to
evaluate the contribution of organic solvent exposure to the risk of non-Hodgkin's lymphoma.
Persson et al. [36] studied 54 cases of Hodgkin's disease, 106 cases of non-Hodgkin's
lymphoma and 275 controls of both genders. The cases were diagnosed in the years 1964-
1986, but only those who were still alive in 1986 were included. The authors did not ask
specific questions about phenoxy acid use. Wingren et al. [37] studied 96 men with soft-
tissue sarcomas diagnosed in the years 1975-1982, 450 general-population controls and 200
cancer controls. Because the results did not differ substantially between the two control
groups, only those obtained from analyses with the general-population controls are reported
here. The authors had to resort to job associated uses of which one was called "unspecified
chemical work, potential exposure to phenoxy herbicides and chlorophenols." because only
limited information could be obtained about specific chemical exposures from postal
questionnaires and selected, supplemental telephone interviews.
Results from these three studies are summarized in Table 8. Persson et al. [36] found
strong associations, Wingren et al. [37] found an association of intermediate strength, and
Olsson and Brandt [35] found very little association. These studies are limited by the lack of
specificity in their exposure information.
United States
Zahm, Cantor and colleagues from the National Cancer Institute have reported results
from three case-control studies in four Great Plains states [38-40]. The first study was
conducted in Kansas [38]. It included soft-tissue sarcomas, Hodgkin's disease, and non-
Hodgkin's lymphomas, but detailed analyses were confined to the non-Hodgkin's lymphomas.
The two subsequent studies, one conducted in eastern Nebraska [39] and the other in Iowa
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and Minnesota [40], contained only non-Hodgkin's lymphomas. These studies did not
consider chlorophenol exposures and only those persons who ever lived or worked on a farm
were asked questions about pesticide exposures. Thus, all non-farmers were considered
unexposed. As in southern Sweden (Table 6), the vast majority of phenoxy acid exposures
did not involve 2,4,5-T and those that did virtually always involved 2,4-D as well. The
relevance of these studies to the focus on TCDD and related compounds in the present review
is therefore somewhat limited.
Results for 2,4,5-T from the three studies are summarized in Table 9. Among ah1
subjects and among farmers, only the study in eastern Nebraska [39] suggests an increase in
risk. All three studies were conducted with virtually identical methods and no information on
herbicide application methods in any of the reports indicate any exposure conditions peculiar
to eastern Nebraska.
The third set of relative risk estimates in Table 9 were computed using the
investigators' procedure of including only the exposed farmers and the unexposed non-
farmers, with the unexposed farmers excluded. This procedure would maximize biases of
case finding, control selection or confounding related to differences between farmers and non-
farmers. In these analyses, the relative risk estimates from the studies in Kansas, Iowa and
Minnesota are somewhat higher and the estimate from the eastern Nebraska study is
somewhat lower than in the two more conventional analyses.
Formal homogeneity tests across the three studies yield two-tailed p-values of 0.4 in
the analysis of all subjects, 0.3 in the analysis restricted to farmers, and 0.6 in the third
analysis. Ordinarily, especially considering the virtually identical methods used in the three
studies, these results would be considered sufficient justification to compute summary
estimates. Summary (maximum-likelihood) estimates of relative risk are virtually identical in
all three groups of subjects, with point estimates of 1.2, lower 95 percent confidence limits of
0.8, and upper 95 percent confidence limits of 1.7 to 1.8.
Woods and colleagues [42] conducted a study of soft-tissue sarcomas and non-
Hodgkin's lymphomas in western Washington State. In this study, the principal method of
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phenoxy acid and chlorophenol exposure assessment was to place job titles, activities and
chemical preparations reported during interviews into categories of potential exposure. The
categories were created "in consultation with local industrial and university representatives
who had had long-term experience with forestry, wood products, and agricultural industries in
the Pacific Northwest" [42]. No statement is given about the relative prevalence of 2,4-D and
2,4,5-T among the phenoxy acids used in this region.
The results (Table 10), show no association between soft-tissue sarcomas or non-
Hodgkin's lymphomas and estimated potential for exposure to phenoxy acids or
chlorophenols. The authors did report, however, that the relative risk of non-Hodgkin's
lymphomas associated with more than 15 years of potential exposure to phenoxy acids
increased with time since the accumulation of that exposure. The relative estimates were 1.3
(95 percent confidence interval 0.9 - 2.2) for exposures more than five years before diagnosis,
1.7 (95 percent confidence interval 1.0 - 2.8) more than 15 years, and 2.5 (95 percent
confidence interval 0.5 - 13.0) more than 25 years. The-authors stated that similar trends
were not seen in any of the analyses of soft-tissue sarcomas and phenoxy acids or of either
cancer in connection with chlorophenol exposures. It is not possible with the available data
from this study to conduct analyses restricted, to persons who worked in forestry, agriculture,
and the wood products industry, and in which the exposed persons are those who reported
specific exposures to phenoxy acids or chlorophenols.
The western Washington State Study reported two unique results. One consisted of
elevated relative risks in connection with self-reported histories of chloracne: 3.3 (95 percent
confidence interval 0.8 - 14.0) for soft-tissue sarcomas and 2.1 (95 percent confidence interval
0.6 - 7.0) for non-Hodgkin's lymphomas. The diagnoses were not medically confirmed and,
because only one percent of all cases and controls reported chloracne histories, the confidence
intervals were extremely wide. The other intriguing result consisted of elevated relative risks
of soft-tissue sarcomas among persons with Scandinavian surnames (12 percent of the cases
and controls). The estimates from this analysis were 2.8 (95 percent confidence interval 0.5 -
15.6) for "high" estimated potential for phenoxy acid exposure and 7.2 (95 percent
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confidence interval 2.1 - 24.7) for "high" estimated potential for exposure to chlorophenols.
The authors noted that similarly elevated relative risks were not found for non-Hodgkin's
lymphomas.
The major problem with U. S. case-control studies is that specific exposure to TCDD
and related compounds is not identified or quantified. In some, only potential exposure to
phenoxy herbicides is the exposure surrogate. This limits the usefulness of these studies.
New Zealand ;
Smith, Pearce and colleagues conducted two studies of soft-tissue sarcomas [43-46]
and one study of non-Hodgkin's lymphomas [47,48] among men in New Zealand. In these
studies, persons were first asked whether or not they "had worked in particular occupations in
which there was potential for exposure to phenoxyherbicides or chlorophenols" [45]. If the
response was affirmative, "a series of subsidiary questions were asked to clarify the work
done and the actual potential for exposure, firstly in general terms, and then in specific terms,
*
seeking the identity of the chemicals used" [47]. The authors indicated that 2,4,5-T was
widely used as a phenoxy acid herbicide in New Zealand over the years pertinent to these
studies (i.e., prior to the early 1980s) [45]. Thus, in these studies, the phenoxy acid exposure
designation may be considered a suitable indicator of exposure to 2,4,5-T and, thus, to TCDD.
Typical uses of 2,4,5-T were in the spraying of gorse, blackberry, pasture, cereal and peas.
In the analyses of phenoxy acids, the authors distinguished between "potential" and
"probable or definite" exposure. The latter category was created by deleting persons with
only "possible" exposures from those with "potential" exposures. It is not clear whether the
"probable or definite" designation included inferences from job tides, activities, and the like,
or whether it was based solely on affirmative responses to specific questions about phenoxy
acid exposures. For chlorophenols, only the "potential" designation was employed.
In these studies, the controls were patients diagnosed with other cancers. As opposed
to a control group selected from the entire study population, a cancer control group offers less
certainty about the degree to which its exposure distribution represents that of the study
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population, but greater certainty that bias from differential exposure misclassification were
negligible. In these particular studies, the cancer controls had an additional advantage in
minimizing any bias that might have resulted from the inability of the researchers to include
patients diagnosed at private hospitals. In an interim report of the non-Hodgkin's lymphoma
study, a second control group was drawn from the New Zealand electoral roll. The authors
concluded that this control group "gave very similar findings to those obtained with the main
control group of other cancer patients" [47].
Another unique feature of the New Zealand soft-tissue sarcoma studies is that, like the
mortality follow-up studies of chemical manufacturing and processing workers previously
reviewed, they included only those cases classified to the International Classification of
Diseases [49] category 171, malignant neoplasms of the soft and connective tissues. This
category, which does not include soft-tissue sarcomas occurring in parenchymatous organs
such as the stomach or uterus, accounted for about 60 percent of the soft-tissue sarcoma cases
in the studies in Sweden [50]. There is no indication from the Swedish studies, however, that
the associations with phenoxy acids or chlorophenols differed between soft-tissue sarcomas
that would be classified in category 171 and those that would be classified in the categories
for the involved organs [21-24, 30].
In the New Zealand Study investigators divided their soft-tissue sarcoma research into
two studies with very similar, but not identical, methods. The first study [43-45] consisted of
patients and controls with cancer registrations in the years 1976-1980. The second study [46]
extended case-finding through 1982 and was the subject of an extremely abbreviated report.
The controls in the second study consisted of 315 of the 338 cancer controls from the non-
Hodgkin's lymphoma study [48], whose cancer registrations were during the period 1977-
1981. (The results for the additional 23 controls, who were interviewed near the end of the
non-Hodgkin's lymphoma study, evidently were unavailable at the time the analyses for the
second soft-tissue sarcoma study were conducted,)
The first sarcoma study [43-45] reported very similar results for phenoxy acids and
chlorophenols when all subjects were included in the analyses, with relative risk estimates of
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1.3 for any "potential" exposure and 1.6 for exposures ("definite or probable" for phenoxy
acids, "potential" for chlorophenols) lasting more than one day and occuring more than five
years prior to diagnosis (Table 11). For phenoxy acid exposures classified by the latter
definition, sufficient data were presented to permit an analysis restricted to farmers. Thirty of
the 82 cases, 13 of the 17 exposed cases, 44 of the controls and nine of the 13 exposed
controls were farmers. Thus, the estimated relative risk is 3.0 (95 percent confidence interval
1.1 - 8.3) among farmers. Controlling for farming by ("indirect") standardization yields an
estimate relative risk of 1.9 (95 percent confidence interval 0.8 - 4.5). Thus, as in some
studies previously reviewed, accounting for the farmer/nonfarmer distinction has a material
impact on the results from this study.
Very few details were presented for the second sarcoma study [29]. In comparison
with a relative risk of 1.6 in the first study, the second study reported a relative risk of 0.8 for
the principal measure of phenoxy acid exposure (Table 11, homogeneity-test p-value = 0.2
contrasting the two studies). The exposure prevalances in the two control groups were
virtually identical (14.1 percent in the first study and 14.6 percent in the second), but the
prevalences in the two case groups differed greatly (exposure odds ratio = 10.0, 95 percent
confidence interval 3.3 - 31.9). Because of this difference, and because a relative risk
estimate restricted to farmers cannot be computed with the data available from the second
study, aggregation of the results would not be warranted.
The non-Hodgkin's lymphoma study [47,48] reported little or no association with
phenoxy acids and a somewhat stronger association with chlorophenols (Table 11). The latter
association did not increase when the more restrictive measure of exposure was used. The
various activities involving exposure to chlorophenols include the treatment of fence posts as
weU as treating pelts in meat works tanneries. Data that would permit an analysis restricted
to farmers were not reported.
The authors emphasized the fact that herbicide spraying is a full-time occupation in
New Zealand and that none of the soft-tissue sarcoma or malignant lymphoma cases had been
commercial sprayers. Smith et al. [45] estimated the prevalence of current and former
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commercial sprayers at approximately 1,500, which would be 0.17 percent of the male
population of New Zealand in the early 1970s [51]. On the null hypothesis, therefore, only
about 0.1 commercial sprayers would be expected among the cases in each of the two soft-
tissue sarcoma studies and about 0.3 commercial sprayers would be expected among the non-
Hodgkin's lymphoma cases. Thus, soft-tissue sarcoma risk could have been increased
manyfold and non-Hodgkin's lymphoma risk could have been increased about threefold
before even one commercial sprayer would be expected in any of the case groups. As a
consequence, the absence of commercial sprayers in any of the case groups is not strong
evidence against an effect.
In a study of 9 selected applicators in New Zealand who had sprayed herbicides for a
minimum of 180 months (and hence 2,4,5-T), Smith et al [88] found a high correlation
between tissue levels of TCDD and months sprayed. This is analogous to Fingerhut's finding
that tissue levels of TCDD correlate well with duration of employment in the herbicide
manufacturing industry. However, he concluded based upon his analysis that brief exposures
to TCDD probably does not contribute to the increased cancer risks seen in studies in other
countries. While an interesting reference, this conclusion may be somewhat overstated
without some information regarding what the tissue levels of TCDD were in the individual
cases and controls of those other studies, information which is only recently becoming
available and not for all studies. Furthermore, there may be considerable differences in
applicator practices between New Zealand and other countries. Professional applicators in
New Zealand must be registered with the New Zealand Agricultural Chemicals Board [99].
And although it might appear that they could be expected to receive a great deal of exposure
to TCDD, more than half of the applicators show serum TCDD levels below 50 ppt [99].
Considering that they were spraying 2,4,5-T for 25 or more years until just recently, it seems
to indicate a great deal of care was taken by these applicators to keep their exposures down.
On the other hand, in other countries there may have occurred brief exposures of large
quantities of TCDD-containing herbicides to a few personnel such as in the Ranch Handers
Cohort.
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Italy
Vineis and colleagues conducted a case-control study of soft-tissue sarcomas in three
provinces in northern Italy [52], Phenoxy acid exposure classifications were based on job
information provided on interviews or questionnaires. The assessments were made by "[t]wo
experts with experience in chemical aspects of agriculture." Cases and controls were
classified into three categories: "certainly unexposed," "exposure could not be ruled out"
(abbreviated below as "possibly exposed"), and "certainly exposed." The authors implied that
phenoxy acid herbicides of all types (2,4-D, 2,4,5-T and MCPA) were used in the area during
the periods of interest, but were able to document only the use of 2,4-D and MCPA (MCPA
and MCPP like 2,4-D do not contain dioxin and dibenzofuran impurities). Thus, this study
may have limited relevance to an interest in TCDD exposures.
The study indicated an inverse association between possible or certain phenoxy acid
exposure and soft-tissue sarcoma risk among men, and a positive association among women
(Table 12). This latter association was restricted to women who were alive at the time the
exposure information was collected. (In the other studies in this review in which the results
were stratified by vital status at the time of the interview, no appreciable differences were
found.) As shown in Table 12, when the analysis is restricted to persons who had ever
worked in agriculture ("farmers"), the relative risk among all women is reduced from 1.9 to
1.1. Sufficient data are not available for an analysis that is both restricted to farming women
and stratified by vital status.
The authors offered overmatching by location of residence as an explanation for the
lack of association among deceased subjects. It would be extraordinary for overmatching or
nondifferential misclassification (the latter being the usual explanation when reduced relative
« *
risks are obtained with exposure information from proxy respondents) to be so strong as to
bias a relative risk of 2.4 all the way down to 0.8.
Rice is the principal agricultural crop in the study area and rice weeding was
historically a predominantly female occupation. (Of 29 rice weeders in the study, all but two
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were women.) Rice weeding during the period 1950-1955 was manual and contact with the
phenoxy herbicides was mainly through the skin.
Among all women in this study, rice weeding during the early 1950s is associated with
a relative risk of 2.3 (95 percent confidence interval 0.7 - 7.7). When the analysis is
restricted to women who were farmers, however, the relative risk drops to 1.4 (95 percent
confidence interval 0.3 - 6.5).
Summary
From the standpoint of exposures to TCDD, the most important results from general-
population case-control studies come from those studies conducted in northern Sweden
[21,23,25], central Sweden [24], and New Zealand [43-48]. These studies were conducted in
areas in which high proportions of phenoxy acid exposures involved 2,4,5-T. The exposure-
assessment methods in these studies included the posing of specific questions about particular
chemicals and herbicide preparations. Moreover, for all but the non-Hodgkin's lymphoma
study in New Zealand [47,48], available data permit analyses restricted to farmers and the
other occupational categories within which the relevant exposures predominantly occur.
For soft-tissue sarcomas,, the Swedish studies are perhaps best represented by a relative
risk of 2.3 (95 percent confidence interval 1.0 - 5.4) for phenoxy acids among workers in
agriculture, horticulture and forestry in the study in central Sweden (Table 7) [24]. This is
justified by the following factors: The proportion of exposures to 2,4,5-T was high in this
study; the methods of assessment were better and there were analyses in within relevant
occupational categories. They have in this study tried to derive risk estimates that have
greater validity after taking into account past criticisms.
The relative risk estimate of 3.0 (95 percent confidence interval 1.1 -8.3) for phenoxy
acid exposure among farmers in the first soft-tissue sarcoma study in New Zealand [43-45]
seems to indicate that farming may be a confounder in this study. Indirect standardization for
farming produces a relative risk of 1.9 (95 percent confidence interval 0.8 - 4.5).
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For malignant lymphomas, the case-control studies provide less evidence of a positive
association. The relative risk estimates from the study by Hardell and colleagues [25] were
very high, even among persons employed in the special occupational groups, but this study
was conducted before the researchers had improved their data collection methods. The
studies in New Zealand [47,48], Kansas [38], eastern Nebraska [39], and Iowa and Minnesota
[40] are more consistent with a much smaller increase in risk, or no increase at all, from
exposures to TCDD.
The remaining case-control studies [22,35-37,42] offer mixed results, some suggesting
increases in the risk soft-tissue sarcoma or malignant lymphoma and others suggesting little or
no increase. The informativeness of each of these studies, however, is limited by one or
more of the following important drawbacks: study areas in which most phenoxy acid
exposures did not involve 2,4,5-T, a lack of information on specific chemicals and
preparations to which cases and controls were exposed, and an inability with available data to
conduct analyses restricted to farmers and the other occupational groups in which the
exposures of interest primarily occur. Apparantly, farming as an occupation appears to affect
risk estimates based upon the findings from several studies where occupation is considered
and should be considered as a potential confounder.
STUDIES OF PULP AND PAPER MILL WORKERS
Table 13 summarizes results for cancers of interest from three follow-up studies of
pulp and paper workers. These studies are important because of the potential for exposure to
PCDDs in this line of work. The study by Robinson et al. [53] was of 3,572 persons who
had worked for at least one year between 1945 and 1955 at any of five mills in the states of
California, Oregon or Washington. The study by Jappinen et al. [54] was of 3,454 workers in
the Finnish pulp and paper industry who had worked continuously for at least one year
between 1945 and 1961. The study by Henneberger et al. [55] was of 883 persons who had
worked for at least one year at a mill in New Hampshire. Jappinen et al. [54] studied cancer
incidence. The other two studies were mortality studies.
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Individually and in the aggregate, these studies give little indication of appreciable
increases in the risk of non-Hodgkin's lymphomas, lung cancer or stomach cancer among
pulp and paper mill workers. Overall, the rate of all cancers combined was somewhat lower
than expected. None of the studies examined connective and soft tissue cancers specifically.
Analyses of specific cancers by work location, duration of employment and latency were only
occasionally conducted in these studies. No consistent results were found that would alter
substantially the impression given by the results for the total cohorts. These studies do not
specifically mention exposure to the PCDDs and are not designed to evaluate the risk of
cancer to PCDDs.
Other studies of cancer among paper and pulp workers have been restricted to
information on deaths, using either proportional mortality ratios [56-59] or mortality odds
ratios [60] as measures of relative risk. These studies are not highly informative because they
usually rely on minimal information in death records and because they are subject to an
upward bias due to the "healthy-worker effect" (i.e., a tendency for employed groups to have
favorable total mortality experience and for causes of death other than cancers, when
compared with the general population). The degree of bias in such studies varies, but it can
be appreciable. For instance, in the cohort studied by Robinson et al. [53], 915 deaths from
all causes were observed and 1,150.3 were expected. If the relative risk estimates for
stomach cancer and non-Hodgkin's lymphomas had been computed as proportional mortality
ratios or mortality odds ratios, they would have been 1.5 and 1.7, respectively, instead of the
values of 1.2 and 1.3 that were obtained by from the authors' more valid comparisons of
mortality rates (Table 13).
OTHER STUDIES
Studies of pesticide applicators are not informative because they contain little
information on specific compounds and preparations to which individual persons were
exposed and as such there is no evidence of exposure to TCDD. Studies with no information
of this type include studies of licensed pesticide applicators by Wang and MacMahon [61],
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Barthel [62], Blair et al. [63], Wiklund et al. [64] and Corrao et al. [65] and a study of
gardners by Hansen et al. [66]. These studies contribute little or nothing to the discussion of
TCDD or compounds like TCDD.
Axelson and Sundell assembled a cohort of 348 Swedish railroad workers who had
applied amitrol, 2,4-D and 2,4,5-T [67]. In the most recent report [68], 17 deaths from
tumors were observed (11.85 expected, relative risk 1.43, p=.09). The relative risk estimate
for lung cancer was 1.4 (three observed deaths, p=.37) and the estimate for stomach cancer
was 2.2 (three observed deaths, p=.15). Again as in most studies, no actual measurements of
TCDD are available from this paper. Only potential exposure to the herbicides 2,4-D and
2,4,5-T are mentioned without any effort to quantify the exposure.
Riihimaki et al. followed a cohort of 1,971 Finnish men who had applied 2,4-D and
2,4,5-T [69,70]. With allowance for a 10 year latency period, 20 cancer deaths were observed
(24.3 expected, relative risk 0.8, 95 percent confidence interval 0.5 - 1.2). The relative risk
for lung cancer was 1.1 (12 deaths observed, 95 percent confidence interval 0.6 - 1.8). The
author points out that because of limitations in the study materials only powerful carcinogenic
effects are likely to be seen.
Vietnam Veterans
Distributions of TCDD levels in serum and adipose tissue are typically
indistinguishable between Vietnam veterans and comparison populations unless the Vietnam
veteran group has been carefully defined on the basis of military records to have engaged in
activities known to have involved herbicide exposure [71-77]. Thus, the mere designation,
"Vietnam veteran," is insufficient as an indicator of exposure to 2,4,5-T or TCDD exposure.
This conclusion is also supported by Stellman and Stellman's review of military records for
the purpose of developing an Agent Orange exposure index [78]. Stellman and Stellman
drew the further conclusion that "it is impossible to give any credence to any health effects
study in which assignment of herbicide exposure levels to individual veterans is based solely
on self-reports" [78]. It is also insufficient to base an exposure index among Vietnam
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veterans on such crude information as military branch (Army, Marine, etc.), corps, or region
' of duty within Vietnam. Thus, a large number of studies of cancer experience among
Vietnam veterans are uninformative from the standpoint of hypothetical effects of TCDD.
These include studies by Breslin et'aL [79], the Centers for Disease Control [80], Dalager et
al. [81], Fett et al. [82], Greenwald et al. [83], Kang et al. [84,85], Kogan and Clapp [6],
Lawrence et al. [86], and O'Brien etal. [87].
The only study of cancer among Vietnam veterans at present with adequate
information on activities involving TCDD exposure is a small mortality study by Michalek et
al. of 1,261 Air Force veterans of Operation Ranch Hand [88]. These persons were
responsible for the aerial herbicide spraying missions in Vietnam. The researchers compared
the Ranch Hand group with a group of 19,101 other Air Force veterans who were mainly
involved in cargo missions in Southeast Asia and who did not have herbicide exposure. A
total of 25 cancer deaths were observed in the Ranch Hand cohort (23.6 expected, relative
risk 1.1, 95 percent confidence interval 0.6 - 1.5). Rates of all specific cancers of interest in
this review were equal to or less than the rates in the comparison group. Serum TCDD
measurements were taken on a small subset (147 herbicide loaders and herbicide specialists)
of the cohort believed to have suffered the most massive exposures. A few of these Ranch
Handers, 5 to be exact, exibited tissue levels above 200 ppt of TCDD but the median serum
level was 26 ppt. in the 147 while the median serum level in 50 controls averaged 5 ppt. [97].
The vast majority of the Ranch Handers probably received less exposure. A more appropriate
group in which to observe effects are members of the South Vietnamese Army who did the
mainstay of the spraying around the perimeters of the military bases in Vietnam. Such a study
has been suggested by Arnold Shecter but current diplomatic roadblocks are preventing this.
Residents of Seveso, Italy
Residents of Seveso, Italy were exposed to 2,3,7,8-TCDD in a chemical accident in
1976. This group is important because of the high exposures, with approximately 200 cases
of chloracne reported [14]. Children [89] and adults [90,91] at the time of the accident are
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being studied separately. The group residing in the zone of highest estimated exposure
consists of 556 adults and 306 children. The group residing in a zone of intermediate
estimated exposure is larger, with 3,920 adults and 2,727 children. The group with lowest
estimated exposure is larger still, with 26,227 adults and 16,604 children. The accuracy of
the three estimated exposure zones has been questioned [14,92,93], especially because the
ranking does not seem to correspond to the occurrence of chloracne in the area.
Consequently, only results for residents of all three zones combined are presented here.
There is no question that at least some of the residents of the most heavily exposed
area (zone A) received massive exposure to 2,3,7,8-T [96]. Up to the time of the analysis in
1990, based upon tissue specimens taken in 1976, just after the accident the highest detected
levels were recorded. Three children at the time who subsequently developed severe
chloracne had serum 2,3,7,8-T levels of 17,274, 27,032 and 27,821 ppt. Two other persons
with severe chloracne exibited levels that were similar to those of 4 other residents of zone A
who did not develop chloracne as follows: for those with chloracne, the readings were 828
and 1688 ppt: for those without chloracne the serum levels were 1772, 3054, 3729 and
10439 ppt. [96].
Thus far, the population has been followed for only 10 years [89-91]. Ten cancer
deaths, two few to support a meaningful analysis of specific cancers, have been among
observed children [89]. Results for the cancers of interest among adults are summarized in
Table 13 [90]. No excesses of mortality from lung cancer, stomach cancer or all cancers
combined are apparent. A moderate and statistically imprecise elevation in the death rate
from a subset of the cancers that make up the non-Hodgkin's lymphomas is evident in the
second five-year period of follow-up. An excess of greater relative magnitude, but even more
imprecisely estimated, hi mortality from cancers of connective and soft tissues appears to
have occurred in the same time period. Because the exposed Seveso residents have been
followed for only 10 years since first exposure, highly informative results will not come until
additional time has elapsed.
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Rice Oil Poisonings in Taiwan and Japan-Compounds Structurally Related to Dioxin
This section discusses two similar incidents involving ingestion of rice cooked with
oils accidently poisoned with polychlorinated biphenyls (PCBs) and polychlorinated
dibenzofurans (PCDFs). PCBs and PCDFs are structurally similar to the polychlorinated
dioxins, and some of these are considered to be dioxin-like in their activity. The dioxin-like
effects of these compounds are felt to be mediated through a cytosolic receptor [101,102,103].
The dioxin-like polychlorinated biphenyl congeners, the 75 chlorinated dioxins and 135
chlorinated dibenzofurans appear to induce similar effects in both animals and humans but
appear to differ quantitatively in toxicity [104, Ahlborg, chapter 3, this document, 105]. They
appear to harm growth and reproduction, they may damage the immune system, they are also
appear to cause cancer. These same effects have been observed in a number of different
species including humans.
Two accidents involving contamination of ingested food from PCBs and
dibenzofurans, the Yusho and Yu-Cheng incidents, have been reported. The Yusho incident
involved 1900 people who in 1968 accidentally consumed up to 2 grams each of PCBs that
had leaked into the rice oil at the facility where the rice oil was canned. The PCBs -were
primarily Kanechlor 400 that had been used as a heat exchange medium thousands of times.
Commercial preparation Kanechlor 400 had a concentration that was 49% chlorinated. The
use of this medium for exchange of heat resulted in an increase in the dibenzofuran
contamination approximately 250 times. The final mixture that was actually present in the
rice oil had a ratio of one molecule of dibenzofuran to every 200 molecules of PCBs.
These victims suffered many ill effects from then* one-time exposure. Tissue studies
by the Japanese of the victims indicated that both the PCBs and PCDFs are retained for many
years after the initial exposure. However, the PCDFs are eliminated at a slower rate.
Concentrations measured several years following the Yusho accident indicated that the ratio
of PCDFs to PCBs remaining in the adipose tissue of the victims was about 1 to 4 [106].
Japanese researchers have attributed most of the non-cancer toxic effects to the presence of
the PCDFs although these effects are consistent with PCB exposure. These toxic effects
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include comedo formation, acneform eruptions, hyperpigmentation, and hyperkeratosis. In
addition, occular lesions such as swollen meibomian glands filled with yellow infarct-like
material and pigmentation of the conjunctiva were seen.
The most notable finding reported by Kuratsune [107] is a significant increased risk of
liver cancer in male victims (9 observed versus 1.6 expected; SMR=559, p<.01) and a non-
significant increased risk in female victims (2 observed versus 0.66 expected; SMR=304).
Additionaly, a significantly increased risk of lung cancer in male victims (8 observed versus
2.45 expected; SMR=326, p<.01). This followup period was 15 years after the accident. The
author reports that the elevated risk of liver cancer remained significant even after the
influence of latency, alcohol consumption and liver disease have been evaluated. Kuratsune
reports that because there was an uneven distribution of deaths in the two provinces affected,
it was too early to draw any conclusions. "Such a markedly uneven geographical distribution
of deaths can hardly be explained by exposure to the toxic rice oil alone." However, he
cautioned that his findings suggest that the poisoning might have caused liver cancer at least
in male patients. He concludes "Our findings should not be disregarded, however, because
the hepatocarcinogenicity of PCBs in animals has been well documented."
An outbreak of illness similar to Yusho was reported among some 2000 persons in the
Taichung and Changhwa provinces of Taiwan in March 1979. The illness consisted of
chloracne, hyperpigmentation and meibomian gland dilatiation. In October 1979 the illness
was found to be the result of the ingestion of cooking oil contaminated with polychlorinated
biphenyls. Chen et al. [107] reported on blood PCS levels of 66 victims for which they had
prepared gas chromatograms. Basically, blood concentration residues ranged from 11 to 720
ppb in these patients. The mean value was 49 ppb; most values were under 100 ppb. In only
two instances were the concentrations greater at 120 and 720 ppb. The authors reported that
the higher value of 720 ppb occurred in a patient who had difficulty in metabolizing and
excreting PCS components. They also maintain that blood PCB levels of these patients are
"much higher" than those of 72 Japanese Yusho patients [108]. Koda and Masuda reported
the mean PCB value in Yusho patients was 5.9 ppb with a standard deviation of 4.5 ppb in
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(year). Chen et al. [107] maintained that this difference is due to a lengthy time lapse from
the exposure to PCS in Yusho patients before measurements were taken compared with a
much shorter time lapse in Yu-Cheng patients. Furthermore, the patients of Yu-Cheng
consumed a larger proportion of higher chlorinated PCBs compared with those of Yusho and,
as a result, they will be retained longer in the body according to the authors. Ten years have
now passed. Researchers should start taking a close look at this cohort now that the latent
period has almost been achieved for liver cancer.
Non-cancer toxic effects resulting from transplacental exposure to the cooking oil in
children born to exposed mothers noted by Rogan et al [109] after the incident were as
follows: Exposed children appear to be shorter and lighter, they have developmental
abnormalities, as well as deficits in formal developmental testing and behavioral assessments.
The Agency has developed the concept of "Toxicity Equivalence Factors" that provide
a basis for estimating the relative toxicity of each polychlorinated dibenzo-p-dioxin and
dibenzofuran relative to that of 2,3,7,8-TCDD [110]. The CDD/CDFs and their toxicity
equivalence factor of most toxic concern are given in table XX.
CONCLUSIONS
Of all the cancers examined in both the case-control and follow-up studies, STS
provides the strongest evidence of an association with TCDD. The original report by Hardell
and colleagues [21] of an association between STS and exposures involving TCDD
contaminated phenoxy herbicides has stood up to extensive criticism and a great deal of
subsequent research. The degree of increased risk, as estimated in later studies by Hardell's
research group and several others, does not appear to be as great as originally indicated, but
the association with TCDD exposure appears more certain. Moreover, no persuasive case has
been made that the entirety of the association in these studies is due to selection bias,
differential exposure misclassification, confounding or chance.
Not every study that has looked for an association between TCDD exposure and soft-
tissue sarcoma risk has found one, but several studies of sound design and adequate size have
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done so to a greater or lesser extent. The results from the important cohort study by
Fingerhut et al. [8] of 5,000 chemical production and processing workers exposed to TCDD
are corroborative, as are those and from the second five years of follow-up of the persons
exposed to TCDD in Seveso [90]. The large IARC Registry cohort study also suggested an
association between STS and phenoxy herbicide exposure, but the TCDD exposure component
was less certain. The first New Zealand sarcoma study [44,45] also appeared to produce
positive results when the analysis, presented above, was restricted to farmers to minimize
bias. These results were produced by independent investigators using substantially different
research methods and studying populations exposed under conditions much different from
those in the studies by Hardell and colleagues, with TCDD exposure being the common link.
The evidence on malignant lymphomas in connection with TCDD exposure is far less
compelling and recent evidence fails to confirm the early finding of Hardell and colleagues,
who conducted only one case-control study of NHL [25], during the early stage of their
research. The evidence from the industrial cohort studies, including the large Fingerhut et al,
[8] and Saracci et al [94] cohorts, and from the Seveso cohort suggest little if any evidence of
increased risk. The limited evidence on TCDD exposure that can be extracted from the
extensive case-control studies on NHL by the National Cancer Institute [38-40] also does not
indicate a consistent and pronounced increase in risk. It would be interesting to see results
restricted to farmers from the New Zealand study of NHL. At the present time, however, the
existing research does not present even a minimally consistent picture of increased risks of
malignant lymphoma among persons most probably exposed to TCDD.
The evidence for lung cancer and TCDD exposure comes from the three recent cohort
follow-up studies [8, 17, 18] all of which provided good TCDD exposure surrogates and some
actual TCDD serum level samples. All three studies showed increased risks of borderline
statistical significance of about 40% - 100% in their highly exposed groups, and low risks in
their less exposed groups. In addition to the above studies, the report of a significantly
increased lung cancer risk in the Japanese rice oil poisoning cohort [Kuratsane, 1988] is also
suggestive of a TCDD-like effect. While confounding by smoking cannot be excluded, the
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limited analyses conducted suggest that smoking cannot explain the entire increase and that
the association is real.
The evidence for an association with stomach cancer is less than that for lung cancer.
While the high exposure/long duration cohorts in both the Fingerhut and Manz studies suggest
increased risks of at least 40%, the estimates are based on too few deaths for any conclusions
to be made. There are no case-control studies relating to TCDD exposure and either lung or
stomach cancer.
While males comprise all the case-control studies and the bulk of the cohort study
analyses, animal and mechanism studies suggest that males and females might respond
differently to TCDD, which reduces estrogen levels in reproductive tissues and reduces
estrogen receptor binding in rat and mouse liver. These antiestrogenic effects are thought to
be responsible for decreased tumor incidences seen in the mammary gland, uterus and
pituitary of TCDD-treated female rats, and may also be responsible for increased liver cancer
in female but not male rats (see Sections 6.4.1 and 6.5.4). These rat liver tumors may be
ovary-dependent, while at the same time the ovaries appear to protect against TCDD-mediated
tumor promotion in the rat lung (see Section 6.4.2). Thus, these complex hormone-dependent
mechanism(s) might very well affect human carcinogenic males and females differently. The
only reported female cohort with good TCDD exposure surrogate information, was that of
Manz et al [17], which had a borderline statistically significant increase in breast cancer.
While Saracci et al [94] did report reduced female breast and genital organ cancer mortality,
this was based on few observed deaths and chlorophenoxy herbicide, rather than TCDD
exposures. In sum, TCDD cancer experience for women is expected to differ from that of
men but presently there are very few results.
Other TCDD related hormonal effects, including immune suppression, may result in
multi-organ sensitivity and may be responsible for the overall increased mortality from all
malignancies combined seen in all four cohort production worker subcohorts with higher
estimated TCDD exposures [8, 17, 18, 94]. These increased relative risks, while not large
(10% to 70%) are consistent and are either statistically significant or of borderline
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significance. While no one tissue site can account for this observed increase, lung cancer is
also increased in three of these.
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Yusho patients: A preliminary report. In: Miller RW, et al., eds. Unusual occurrences
as clues to cancer etiology. Japan Sci Soc Press: Tokyo/Taylor & Francis, Ltd., 1988;
pp. 61-68.
101. Poland A. Reflections of the mechanism of action of halogenated aromatic
hydrocarbons. Banbury Rep. 1984;18:109.
102. Poland A, Glover E, Taylor B.A. The murine Ah locus: A new allele and mapping to
chromosome. Mol Pharmacol 1987;32:471.
103. Goldstein JA., Safe S.- Mechanism of action and structure-activity relationship for the
chlorinated dibenzo-p-dioxins and related compounds. In: Kimbrough RD., Jensen AA,
eds. Halogenated biphenyl, terphenyl, naphthalenes, dibenzodioxins and related products.
Elsevier, Amsterdam; p. 239.
104. McConnell EE. Acute and chronic toxicity and carcinogenesis in animals. In:
Kimbrough R.D., Jensen A.A., eds. Halogenated biphenyls, terphenyls, naphthalenes,
dibenzodioxins and related products. Elsevier, Amsterdam; p. 161.
105. Schecter A. Dioxins and related chemicals in humans and in the environment. In:
Banbury Rep. 35: Biological basis for risk assessment of dioxns and related compounds.
Cold Spring Harbor Laboratory Press: 1991; pp. 169-214.
106. Kuratsune M, Masuda Y, Nagayama J. Some of the recent findings concerning Yusho:
proceeding of National Conference on Polychlorinated Biphenyls; Nov 19-21, 1975;
Chicago.
7-51
09/10/92
-------
DRAFT-DO NOT CITE OF QUOTE
107. Chen PH., Gaw JM., Wong CK.,' Chen CJ. Levels and gas chromatographic patterns of
polychlorinated biphenyls in the blood of patients after PCB poisoning in Taiwan. Bull
Environ Contam Toxicol 25:325-329.
108. Koda H, Masuda Y. Relation between PCB level in the blood and clinical symptoms of
Yusho patients. Fukuoka Igaku Zasshi 1975;55(10):624-628 (in Japanese).
109. Rogan WJ, Gladen BC, Hung KL, Koong SL, Shih LY, Taylor JS, Yu YC, Yang D,
Ragan NB, Hsu CC. Congenital poisoning of polychlorinated biphenyls and their
contaminants in Taiwan. Science 1988;241:334.
110. U.S. Environmental Protection Agency (EPA). Interim procedures for estimating risks
associated with exposures to mixtures of chlorinated dibenzo-p-dioxins and dibenzofurans
(CDDs and CDFs). Washington, DC. 6253-89:12.
7-52
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DRAFT-DO NOT QUOTE OR CITE
HEALTH EFFECTS OTHER THAN CANCER
INTRODUCTION
Among humans the most frequently described 2,3,7,8-TCDD exposure-associated
conditions involve the skin, liver, and neurologic systems, and disturbances of the
gastrointestinal, genitourinary, endocrine, cardiovascular, pulmonary, and immunologic
systems, as well as increased incidence of some malignancies. The majority of effects were
reported among occupationally exposed groups, including chemical production workers,
pesticide users, and individuals handling or exposed to materials that have been treated with
2,3,7,8-TCDD-contaminated pesticides, and among residents of communities contaminated
with tainted waste oil (Missouri, USA) and industrial effluent (Seveso, Italy).
DESCRIPTION OF MAJOR STUDIES
The information describing human health effects attributed to exposure to
2,3,7,8-TCDD-contaminated materials is derived from a wide variety of sources including
clinical assessments (case reports) of exposed individuals and analytic epidemiologic studies
using case-control, cross-sectional, and cohort mortality designs. The case reports describe
the acute outcomes of exposure to 2,3,7,8-TCDD and provide the bases for hypothesis
generation for controlled epidemiologic studies, but they are not suitable for testing causal
relationships between exposure and related health effects (Ashe and Suskind, 1950; Suskind et
al., 1953; Bauer et al., 1961; Goldman, 1973).
Cross-sectional studies, which included a medical examination of potentially exposed
workers, have assessed the prevalence of diseases or conditions reported to be associated with
exposure to TCDD. Although, earlier studies used unexposed control groups for comparison
(Suskind and Hertzberg, 1984; Moses et al., 1984; Lathrop et al., 1984; Lathrop et al., 1987);
they were unable to relate exposure to materials contaminated with 2,3,7,8-TCDD with
specific diseases or causes of death. This inability to define an exposure-outcome relationship
is due to a variety of shortcomings in the studies, including small sample size, poor
7-68
09/10/92
-------
DRAFT-DO NOT QUOTE OR CITE
participation, short latency periods, selection of inappropriate controls, and the inability to
quantify exposure to 2,3,7,8-TCDD or to identify confounding exposures.
More recent cross-sectional studies of workers by the National Institute for
Occupational Safety and Health (NIOSH) and of Ranch Hand personnel by the United States
Air Force have evaluated TCDD-associated health effects in TCDD-exposed populations and
unexposed comparison populations (Wolfe et al., 1991; Sweeney et al., 1991).
NIOSH Study
The study conducted by the National Institute for Occupational Safety and Health
(NIOSH) is a cross-sectional medical study of living workers who were previously employed
for at least one day in one of two plants located in Newark, New Jersey and Verona,
Missouri. From 1951 to 1969, 490 workers employed at the New Jersey plant were employed
in the production of sodium 2,4,5-trichlorophenate (NaTCP), 2,4,5-trichlorophenoxy acetic
acid (2,4,5-T), and 2,4-dichlorophenoxy acetic acid (2,4-D). A high incidence of chloracne
and other dermatologic abnormalities, and cases of porphyria, and hypomania were reported
among the workers at the New Jersey facility [Poland et al., 1971; Bleiberg et al, 1964] which
produced some of the most heavily TCDD contaminated NaTCP and 2,4,5-T among
production facilities whose products were surveyed [Fee et al., 1975]. At the Missouri plant,
NaTCP and 2,4,5-T were produced intermittently for four months in 1968, and NaTCP and
hexachlorophene were produced continuously for twenty two months, between April, 1970
and January, 1972. Prior to this cross-sectional study, the health of the 96 Missouri
production workers had not been previously studied.
For comparison, unexposed neighborhood referents were recruited using a random
sampling procedure described by Sweeney [Sweeney et al., 1989]. Referents were selected if
they reported no prior history of occupational exposure to TCDD, and matched the worker by
age (within 5 years), race and gender. A total of 586 workers were eligible for inclusion in
the study, of which 400 (68.3%) were living, 142 (24.2%) were deceased and 44 (7.5%) could
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not be located. All 400 living workers were invited to participate in the study; 281 (70%)
were examined, description of the study population is included in the results.
Worker and referent health and exposure status was assessed in 1987-1988 through an
interviewer-administered medical and occupational history and comprehensive physical and
psychological examination (Sweeney etaL, 1989). A lifetime medical history was obtained
from each examined participant by interviewers who were blind to the exposure status of the
respondent. Results of the pulmonary, hepatic and gastrointestinal and neurologic
examinations have been published or accepted for publication (Calvert et al, 1991, 1992;
Sweeney et al, 1992). Findings for diabetes and serum glucose level, porphyria, mood
dysfunction, endocrine function and p450 metabolism have been presented in public meetings
(Sweeney et al, 1992; Calvert et al, 1992; Alderfer et al, 1991; Egeland et al, 1992; Halperin
et al, 1992).
As a surrogate for cumulative exposure, serum TCDD levels were measured in 237
workers and a random sample of 79 referents. Procedures for sample collection, preparation,
adjustment for lipids and statistical analysis were described in earlier reports (Fingerhut et al.,
1989; Patterson et al., 1986; Sweeney, 1990]. The mean lipid-adjusted serum TCDD level for
workers was 220 parts per trillion (ppt), median 80 ppt, ranging to 3400 ppt. The mean level
was statistically significantly greater than that for referents (7 ppt) (p<0.001). Analysis of the
other congeners of dioxins and dibenzofurans were also conducted (Piacitelli et al, 1991).
Only the TCDD levels were different in the two exposure groups.
US Air Force Ranch Hand Study
One of the largest and persistent epidemiologic investigations of US military personnel
stationed in Vietnam is being conducted the US Air Force. The study population consists of
Air Force personnel who served in Operation Ranch Hand units in Vietnam from 1962 to
1971 and were employed in the dissemination of Agent Orange through aerial spraying.
Comparisons included Air Force personnel who flew or maintained C-130 aircraft in
Southeast Asia during the same time period.
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The study design includes a series of cross-sectional medical studies conducted at 5
year intervals beginning with the baseline study in 1982 (N=1045 exposed, 1224 unexposed).
Two followup evaluations were conducted in 1985 (N=1016 exposed, 1293 unexposed) and
1987 (N=995 exposed, 1299 unexposed). Each cross-sectional study included comprehensive
physical and psychological evaluations. In the 1982 baseline and 1985 and 1987 followup
studies, exposure based on the comparison of the Ranch Hand group versus the Comparison
group. An additional analysis approximated exposure (low, medium, high) for the Ranch
Hand group using historical military data, and herbicide procurement and usage records. The
results of these analyses were prepared by Lathrop and colleagues (1984 and 1987). In 1988,
serum TCDD levels were measured for a sample of the 1987 Ranch Hand group (N=866) and
the 1987 Comparison group (N=804). The 1987 examination data were then reanalyzed using
lipid-adjusted serum TCDD levels as the relative measure of exposure. The median serum
TCDD level for the Ranch Hand group was 12.8 ppt, ranging to 618 ppt. For the
Comparison group, the median level was 4.2, ranging to 54.8 ppt (Wolfe et al, 1991).
The importance of these studies rests on the fact that serum TCDD levels were
measured for all or a large sample of the subjects, thus confirming the level and extent of
TCDD exposure and permitting the investigators to assess hypothesized dose-response
relationships.
Community residents potentially exposed to TCDD prticularly from Seveso and
Missouri have been studied at length. Of 200 workers employed at the ICMESA plant, in
Seveso, approximately 4% (N=8) were found to have damage to peripheral nerve Fibers of
multiple (unspecified) nerves, controlling for confounding factors such as alcohol abuse,
diabetes, kidney disease, and neurotoxic medication use. In general, the findings of
neurologic abnormalities among exposed community residents are less striking than those
among occupational groups. In 1979, a preliminary report of the two neurologic screenings
conducted in 1977 and 1978 on residents of Seveso and other communities .was released by
Pocchiari et al. (Pocchiari, 1979) (Table 2).
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The following section contains a review of the case reports and epidemiologic studies
that describe health effects associated with exposure to materials contaminated with
2,3,7,8-TCDD.
DERMAL EFFECTS
The most widely recognized dermal effect of exposure to 2,3,7,8-TCDD- contaminated
substances is chloracne (Table 1). Chloracne is a persistent acneiform condition characterized
by comedones, keratin cysts, and inflamed papules with hyperpigmentation and a unique
anatomic distribution, occurring subsequent to acute and chronic exposure to a variety of
chlorinated aromatic compounds (Crow, 1978; Moses and Prioleau, 1985). This acne-like
condition is reported to have occurred with and without other health effects in at least a few
people after all reported accidents at TCP production facilities (Ashe and Suskind, 1950;
Susldnd et al., 1953; Goldman, 1972; May, 1973; Reggiani, 1978; Filippini et al., 1981),
among individuals involved in daily production of 2,3,7,8-TCDD-contaminated products
(Bleiberg et al., 1964; Poland et al., 1971; Pazderova-Vejlupkova et al., 1981; Moses et al.,
1984; Moses and Prioleau, 1985; Suskind and Hertzberg, 1984; Bond et al., 1989) and among
three laboratory workers exposed to pure 2,3,7,8-TCDD (Oliver, 1975).
Other dermal effects included a variety of symptoms and conditions that occurred less
frequently than chloracne but appeared in several groups subsequent to acute and continuous
exposure to TCDD-contaminated TCP and 2,4,5-T. Two reports indicated that after acute
episodes of exposure, e.g. accidents, individuals complained of red and irritated eyes,
conjunctivitis, and blepharitis (inflammation of the eyelids) (Ashe and Suskind 1950; Baader
and Bauer, 1951). Other investigators also found cases of eyelid cysts several months after
acute exposure (Suskind et al., 1953; Kimmig and Schulz, 1957; Poland et al., 1971;
Reggiani, 1980) and up to 25 years after exposure (Suskind and Hertzberg, 1984).
Hyperpigmentation, hirsutism (also known as hypertrichosis or abnormal distribution
of hair) was diagnosed among chemical workers in the United States (West Virginia and New
Jersey) (Ashe and Suskind, 1950; Suskind et al., 1953; Bleiberg et al., 1964; Poland et al.,
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1971), in Germany (Bauer et al., 1961; Goldman, 1972) and in Czechoslovakia (Jirasek et al.,
1974) who were exposed to TCDD-contaminated TCP during manufacturing processes or
industrial accidents, and among laboratory workers in England exposed while synthesizing
pure 2,3,7,8-TCDD (Oliver, 1975). These effects were not seen upon reexamination 25 years
later among workers from the West Virginia plant (Suskind and Hertzberg, 1984; Moses et
al., 1984).
Actinic or solar elastosis was found to be more prevalent among West Virginia
workers diagnosed with active chloracne at the time of their examinations in 1979 (Suskind
and Hertzberg, 1984)(exposed = 59.1%; unexposed = 30.1%, p<.01). Actinic elastosis is
directly related to sun exposure; however, the amount of sun exposure, skin type, or other
factors contributing to the sensitivity of the skin to sunlight was not assessed in the report.
No other studies of TCP production" workers have found an increase in the prevalence of
actinic elastosis. Among this same group, Suskind noted three cases of Peyronie's disease, a
rare condition characterized by progressive scarring of the penile membrane. No explanation
for this finding was expressed nor has the condition been noted (or perhaps looked for) in
other studies.
In 1984, a statistically significant excess of nonmelanotic skin cancer was reported
among Ah- Force personnel involved in the aerial spraying of herbicides over Vietnam
compared with a matched comparison group (Lathrop et al., 1984). The comparison group
was composed of Air Force personnel assigned to cargo missions outside the sprayed areas of
Vietnam. A followup study of the same cohorts in 1987 confirmed the excess of basal cell
carcinoma, and attributed the increase to sunlight exposure (Lathrop et al., 1987). However,
skin neoplasms were not related to serum TCDD level in the reanalysis of the 1987
examination data (Wolfe et al., 1991).
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GASTROINTESTINAL EFFECTS
Liver Size
Changes in liver function and structure after exposure to 2,3,7,8-TCDD are commonly
observed in treated animals. The changes are not always consistent from one species to
another but they prompted examination of hepatic effects among exposed human populations.
As with animals, there is wide variation in the type and degree of hepatic effects reported in
humans after exposure to 2,3,7,8-TCDD-contaminated materials (Table 1).
One symptom that has been consistently reported in the animal literature after
exposure to 2,3,7,8-TCDD is increased liver size. Five studies of humans reported enlarged
liver size. Liver size was increased among TCP production workers in West Virginia
(Suskind and Ashe, 1950; Suskind et al., 1953) and in Czechoslovakia (Jirasek et'al., 1973;
1974) and was found among 5 of 22 Seveso residents with*severe chloracne lasting "several"
months without concomitant elevation in hepatic enzymes (Reggiani, 1980). A twofold
statistically nonsignificant increase in hepatomegaly was found among Air Force Ranch
Banders in the baseline study (Lathrop et al., 1984).
However, Hepatomegaly was not observed in relation to TCDD lelvel in the 1987 followup
(Wolfe et al., 1991). Similarly, Calvert et al. (1992) found no association between serum
TCDD level and liver size in a group of workers exposed to TCDD-contaminated chemicals
more than 15-37 years earlier.
Enzyme Levels
Animal studies have demonstrated changes in hepatic enzyme levels after TCDD
exposure although there is considerable interspecies variation in the observed effect. Seven
studies and case reports reported elevated liver enzymes among exposed workers and among
Seveso residents. Increased levels of gamma glutamyl transferase (GOT) may suggest
activity such as cholestases, liver regeneration, or drug or xenobiotic metabolism. Elevation
in GOT levels was found among Seveso adults (Filippini et al., 1981) (data not shown) and,
among boys living in a more highly contaminated region of Seveso. The children showed a
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12 to 40% increase in GOT levels up to 3 years after the accident (Mocarelli et al., 1986)
(Table 2). In industrially exposed groups, a 20% increase in GOT level was noted among
British TCP workers with chloracne tested 10 years after exposure to 2,3,7,8-TCDD-
contaminated chemical as a result of a TCP reactor explosion (May, 1982; Martin, 1984)
(Table 1). A statistically significant excess in the proportion of individuals with abnormally
high GOT levels was found among West Virginia workers with chloracne who were examined
as many as 30 years after exposure (Moses et al., 1984) (chloracne = 23% abnormal vs. no
chloracne = 9% abnormal, p<.03). In a study by Calvert et al. (1992), increased GOT was
limited to workers from New Jersey and Missouri with high serum TCDD levels and high
lifetime alcohol consumption. The risk increased with increasing serum TCDD levels and
lifetime alcohol use. Only slight increases in mean GOT level (Ranch Handers = 40.1 vs
controls = 39.3) were observed in Air Force Ranch Handers (Lathrop et al., 1984). Yet in the
1987 followup study; serum TCDD level estimated for the date of last exposure (initial dioxin
level) was significantly and positively associated with increased GGT (Wolfe et al., 1991).
Abnormal levels of aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) may indicate liver cell damage from a number of etiologies including hepatic necrosis,
metastatic carcinoma or obstructive jaundice (AST and ALT), or infectious or toxic hepatitis
and cirrhosis (AST) (Henry, 1979). Elevated levels of these enzymes may also be due to
nonhepatic origins, such as myocardial infarction, acute pancreatitis (AST and ALT), or
skeletal,^cerebral, or renal necrosis (AST). Both enzymes were elevated among TCP
production workers in New Jersey (Bleiberg et al., 1964) and in Czechoslovakia (Jirasek et
al., 1974). AST was increased in West Virginia TCP workers with chloracne (3% abnormals
with chloracne vs 0 abnormals without chloracne) (Moses et al.,'1984), and ALT was
increased in 5 of 14 TCP workers from Great Britain who were in the manufacturing building
at the time of a reactor explosion (May, 1973). Filippini et al. (1981) found increased AST
and ALT among adult Seveso residents and Mocarelli et al. (1986) observed a 24% elevation
in ALT levels among male children in Seveso tested 1 year after the accident compared with
unexposed comparisons. None of the studies reported clinical evidence of liver disease in
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these populations. Therefore, in the absence of reports among exposed individuals of hepatic
or nonhepatic diseases related to changes in ALT or AST levels, it is possible that the
fluctuations in enzyme levels may be due to activities related to metabolism of xenobiotics.
Other enzymes, delta amino levulinic acid (d-ALA) (Jirasek et al., 1974), lactate
dehydrogenase (LDH) (Poland et al., 1971; Lathrop et al., 1984) and alkaline phosphatase
(ALK) (Jirasek et al., 1974) were found elevated in one or two groups. No abnormal levels
of ALK, AST, ALT, or GOT were found among West Virginia workers examined by Suskind
and Hertzberg (1984) or among Michigan TCP or 2,4,5-T workers who participated in yearly
medical surveillance examinations between 1976-1978 (Bond et al., 1983), The NIOSH study
found no increased risk of out-of-range values for LDH, total bilirubin, unconjugated
bilirubin, ALK, total protein and albumin, AST, or ALT relative to serum TCDD level
(Calvert et al., 1992).
In some instances, followup studies found that, over time, liver enzyme levels returned
to normal. Ten years after their initial study of the Czechoslovakian TCP workers, Jirasek et
al. (1974) and Pazderova-Vejlupkova et al. (1981) found enzyme levels (ALT, AST, d-ALA,
ALK) in the surviving subjects were not increased. GOT levels in children of Seveso were
normal 3 years after the accident (Mocarelli et al., 1986) and were not elevated in Air Force
Ranch Handers when retested in the first followup study conducted in 1985 (Lathrop et al.,
1987). Yet upon reanalysis GOT appeared to be elevated significantly in relation to TCDD
level (Wolfe et al., 1991). AST levels among the Seveso children also returned to normal
within 6 years after the accident (Mocarelli et al., 1986). Finally, LDH levels found increased
in Ranch Handers in the baseline study were not raised upon reexamination (Lathrop et al.,
1984; Lathrop et al., 1987; Wolfe et al.^1991).
In eleven reports, d-glucaric acid excretion was measured as a possible indicator of
enzyme induction by 2,3,7,8-TCDD but with little consistency in the results. Elevated levels
(chloracne = 2.09 vs unexposed controls = 1.59) were found in chemical workers in England
tested 10 years after exposure to TCDD-contaminated effluent from a TCP reactor explosion
(May, 1982; Martin, 1984). Statistically significant d-glucaric acid excretion was elevated in
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urines collected in 1978 from adults residing in Seveso, Italy, at the time of the ICMESA
accident compared with residents of unexposed communities (Seveso = 27.1 umole/g vs
unexposed = 19.8 umole/g p<.05) and among Seveso children with chloracne (39 umole/g)
compared with those without chloracne (20.5 umole/g) (Ideo et al., 1985). None of the
studies described other exposures or conditions that could have increased d-glucaric acid.
Elevated levels of d-glucaric acid were not observed among individuals exposed to TCDD-
contaminated waste oils in Times Beach or Quail Run, Missouri (Webb et al., 1989; Hoffman
et al., 1986), or among Air Force Ranch Handers (Lathrop et al., 1984; Lathrop et al., 1987;
Wolfe et al., 1991) or chemical workers from West Virginia (Suskind and Hertzberg, 1984;
Moses et al., 1984), New Jersey, or Missouri (Calvert et al., 1991) or among Dutch forestry
workers presumed to be heavily exposed to 2,4,5-T for many years (van Houdt et al., 1983).
Porphyrin Metabolism
Porphyria cutanea tarda (PCT) has been reported in two studies of TCP production
workers (Bleiberg et al., 1964; Jirasek et al., 1974) and among members of a family with
inherited uroporphyrindecarboxylase deficiency (UROD) who were living in Seveso at the
time of the reactor accident (Strik et al.).
PCT is a form of acquired or inherited porphyria caused by a deficiency of the
enzyme uroporphyrinogen decarboxylase (UROD) and the resulting overproduction and
excretion of uroporphyrin (Sweeney, 1986). The predominant characteristics of PCT include
skin fragility, blistering upon sun exposure, dark pigmentation and excess hair growth,
hepatomegaly, reddish-colored urine, and urinary excretion of uro- and
heptacarboxylicoporphyrins (Strik, 1979). PCT has been associated with excessive alcohol
intake, oral estrogens, iron overload, hepatomas, and exposure to polyhalogenated
hydrocarbons (Strik, 1979). A particularly large outbreak of PCT occurred after consumption
of grain treated with hexachlorobenzene (HCB) (Cam and Nigogosyan, 1963). While
2,3,7,8-TCDD has been related to alterations in porphyrin metabolism in mice and rats
(Goldstein et al., 1973; Smith et al., 1981; Jones et al., 1981; DeVerneiul et al., 1983; Cantoni
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et al., 1981; Goldstein et aL, 1982). No PCT was reported among three laboratory workers
exposed to pure 2,3,7,8-TCDD (Oliver, 1975). These individuals are the only humans to have
documented exposure to uncontaminated 2,3,7,8-TCDD.
In 1977, 60 Seveso residents were tested for elevated porphyrins, exclusive of the
family with inherited deficiency of UROD. None of the 60 residents developed PCT;
however, 22% (N=13) exhibited secondary coproporphyrinuria, 5 of whom showed a slight
increase of uro- and heptacarboxyporphyrins and coproporphyrins (Doss et al., 1984).
Porphyrin levels were retested in 1980 and in 12 of the cases porphyrin levels returned to
normal. In three others, porphyrin levels were more severe and were attributed to liver
damage and alcohol consumption. Among the Seveso family with UROD Doss et al. (1984)
suggests that exposure to 2,3,7,8-TCDD-contaminated effluent caused an exacerbation of a
preexisting enzyme deficiency.
In 1964, Bleiberg et al. reported that based on the Watson-Schwartz test, 11 of 29
New Jersey workers with chloracne who were employed in the manufacture of TCP, 2,4,5-T,
and 2,4-D had porphyria cutanea tarda due to increased urinary uroporphyrins,
coproporphyrins, and urobilinogen. In a later study of 73 workers from the same plant,
including four of the individuals that Bleiberg et al. (1964) found to have elevated urinary
porphyrins, Poland et al. (1971) identified one individual with uroporphyrinuria. The report
did not explain if this individual was one of the four described by Bleiberg et al. (1964). The
NIOSH study, which included workers from this same plant, found no increase in porphyria
cutanea tarde. Additionally, there was no association with high body burdens of TCDD for
seroporphyrinuria or coproporphyrinuria (Calvert et al., 1992).
Jirasek et al. (1974) found 11 individuals of 55 Czeckoslovakian TCP workers to have
elevated urinary uroporphyrins that decreased over the observation period; the authors did not
describe the test used to measure urinary uroporphyrins or coproporphyrins. Ten years later,
Pazderova-Vejlupkova et al. (1981) found no evidence of increased excretion of uroporphyrins
or dermatological indications of PCT in the same group of workers.
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There is some doubt that the porphyria noted in the New Jersey (Bleiberg, 1964) and
Czechoslovakian workers was due to 2,3,7,8-TCDD exposure. Jones and Chelsky suggest that
the observed cases of PCT among the TCP workers from New Jersey and Czechoslovakia
may be due to exposure to HCB or a combination of both 2,3,7,8-TCDD and HCB (Jones and
Chelsky, 1986). HCB was manufactured at the New Jersey plant from 1951 until 1960 and
was produced at the facility in Czechoslovakia during the production of pentachlorophenol
(Jirasek et al., 1973).
There is also some question as to the appropriateness of the clinical test Bleiberg et al.
(1964) used to measure porphyrin levels (Watson, 1964). In a letter to the editor, Watson
pointed out that the Watson-Schwartz test was capable of measuring only the presence of
porphobilinogen, that the test was rarely positive in cases of exposure to hepatotoxins, and
suggested that either Bleiberg et al. (1964) used other, but unspecified tests, to measure uro-
and coproporphyrin levels, or that they misinterpreted the function of the Watson-Schwartz
test. No response was made to this observation by Bleiberg or the other authors.
In the NIOSH study which examined workers from the same plant in New Jersey, the
pattern of urinary porphyrin excretion for each participant was assessed to determine the
presence of PCT (Calvert et al., 1992). No difference was found between workers and a
nonexposed control group in the prevalence of PCT (OR = 0.93, 95% CI = 0.19, 4.54).
Furthermore, there were no differences in the risk between workers and the control group for
an out-of-range uroporphyrin concentration or an out-of-range coproporphyrin concentration.
Because this study was conducted at least 15 years after last occupational exposure to TCDD,
it was not possible to determine whether porphyrinuria occurred during the years more
proximal to occupational TCDD exposure.
Evidence of porphyria in other studies of individuals exposed to 2,3,7,8-TCDD-
conta'minated substances is minimal. Although Suskind and Hertzberg (1984) sampled urine
for porphyrins in the examination of West Virginia TCP workers, the specimens were
incorrectly collected and the data not presented. Moses et al. (1984) found no difference in
porphyrin levels when comparing TCP workers with and without chloracne. These data are
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not useful for assessing exposure-disease relationships because both groups may have
contained exposed workers.
In the baseline study of U.S. Air Force Ranch Handers, there was no difference in the
levels of uroporphyrins or coproporphyrins (Lathrop et al., 1984). However, in the followup
study, the mean uroporphyrin level in the comparison group (17.9 mg/24 hrs) was
significantly higher than in the Ranch Handers (16.9 mg/24 hrs, p<.05) (Lathrop et al., 1987).
In contrast, the mean coproporphyrin level in Ranch Handers (119.1 mg/24 hrs) was higher ,
than in the comparison group (115.6 mg/24 hrs); however, the increase appeared to be
strongly associated with age and alcohol use at the time of the study.
It is possible that the PCT and elevated urinary porphyrins observed in the New Jersey
and Czechoslovakian workers was a direct result of exposure to HCB. 2,3,7,8-TCDD,
however, is a potent porphyrigen in rats and mice and, therefore, may have contributed to the'
change in porphyrin levels in these two populations.
Lipid Metabolism
Elevations in various serum lipid fractions have been reported in studies of TCP
production workers and laboratory workers; however, the data are inconsistent among the
studies (Table 1). Total cholesterol and lipid levels were elevated in 50% of the 55
Czechoslovakian TCP production workers examined between 1968 and 1969 (Jirasek et al.,
1974). In a followup study 10 years later, lipid levels among workers removed from
exposure were not significantly different from control levels (selection of controls was not
specified) but total cholesterol levels remained significantly increased (Pazderova- Vejlupkova
et al., 1981). Two independent studies of British TCP workers from the same plant found
elevated triglycerides in exposed workers with (1.97 mmol/1) and without chloracne (1.90
mmol/1) compared to unexposed controls (1.41 mmol/1) (Martin, 1984). Martin (1984) also
found significantly elevated cholesterol levels in exposed workers with (6.02 mmol/l) and
without (6.14 mmol/1) chloracne compared to unexposed controls (5.6 mmol/1), whereas May
(1982) found unexposed workers (6.6 mmol/1) to have cholesterol levels higher than exposed
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workers with chloracne (5.97mmol/l). Martin (1984) also found reduced HDL cholesterol
among exposed workers with chloracne (1.19 mmol/1) compared to unexposed controls (1.25
mmol/1). The differences in the results may be due to differences in the control groups and
inclusion of different workers in the exposed groups.
Cholesterol and triglyceride levels in West Virginia TCP production workers were
compared with unexposed workers from the same plant (Suskind and Hertzberg, 1984). No
difference was identified in mean cholesterol levels and lower mean triglyceride levels
between workers and controls. When lipid fractions were examined, however, there was a
larger percentage of exposed workers with elevated LDL cholesterol (7.7%) compared to
unexposed controls (6.3%). In a second study that compared West Virginia workers with and
without chloracne, no difference was found in mean cholesterol levels although individuals
with chloracne had statistically nonsignificantly increase in mean triglyceride levels (chloracne
= 153.6 mg/dl vs without chloracne = 132.3) (Moses et al., 1984). Three laboratory workers
who were synthesizing pure 2,3,7,8-TCDD developed serum cholesterol levels in excess of
300 ug/dl (Oliver, 1975). Mean cholesterol and triglyceride levels measured yearly from July
26, 1976, through June 30, 1982, were not elevated in children age 6 to 10 years who resided
in the areas of Seveso, Italy, that were most highly contaminated with 2,3,7,8-TCDD when
compared to children living in uncontaminated areas of Italy (Mocarelli et al., 1986) (Table
2).
The effect of exposure to 2,3,7,8-TCDD-contaminated chemicals on lipid or
cholesterol levels is not clearly demonstrated in the available studies. Although the studies by
May (1982), Martin (1984), and Suskind and Hertzberg (1984) used unexposed control
groups, the control groups may not have been appropriate due to age differences (Suskind and
Hertzberg, 1984) and potential for exposure to 2,3,7,8-TCDD-contaminated chemicals (May,
1982; Moses et al., 1984). In addition, none of the studies were able to evaluate preexposure
lipid levels, which would help to confirm an exposure-outcome relationship more
convincingly. Other factors, such as dietary cholesterol intake, familial hypercholesterolemia,
and exercise, which also affect cholesterol and other lipid levels, were not considered in any
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of these studies. The Air Force Ranch Hand Study reported no difference in the various lipid
fractions between exposed and unexposed populations (Lathrop et al., 1984, 1987). However,
when correlated with serum TCDD levels measured at the time of the exam (current level) or
estimated for the time of last occupational exposure (initial level), HDL was significantly and
negatively correlated and the cholesterol/HD ratio was significantly and positively correlated
with serum TCDD (Wolfe et al., 1991). The data from the NIOSH study are currently in
review.
Other Gastrointestinal Disorders
A variety of gastrointestinal disorders other than liver conditions were reported among
TCDD-exposed groups (Table 1). After heavy, acute, or chronic exposure, chemical workers
in West Virginia (Ashe and Suskind, 1950), in West Germany (Baader and Bauer, 1951;
Bauer et al., 1961), and in Czechoslovakia (Jirasek et al., 1974) consistently reported transient
episodes of right upper quadrant pain, loss of appetite, and nausea. None of the reports
suggest an etiology for these symptoms nor were the symptoms reported in later followup
studies of either cohorts (Suskind and Hertzberg, 1984; Moses et al., 1984;
Pazderova-Vejlupkova et al., 1981).
Three investigations of TCP production workers reported increased prevalence of
upper gastric ulcers across all age strata of West Virginian workers (exposed = 20.7% vs
unexposed = 5.5%) (Suskind and Hertzberg) and all digestive system diseases (type not
specified) among workers employed in a plant in Midland, Michigan (prevalence: exposed =
1.5% vs unexposed = 0.5%) (Bond et al., 1983). The factors contributing to these conditions
have not been examined fully. Neither the Ranch Hand study (Wolfe et al., 1991) nor the
NIOSH study (Calvert et al., 1992) found increased risk of upper gastric ulcers with
increasing serum TCDD level.
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ENDOCRINE AND OTHER METABOLIC EFFECTS
A frequently reported symptom of men who were exposed to 2,3,7,8-TCDD
contaminated materials as a result of daily exposure and industrial accidents is reduced libido
(Baader and Bauer, 1951; Suskind, 1953; Kimmig and Schulz, 1957; Bauer et aL, 1961)
(Table 1). Two independently conducted studies of West Virginia TCP workers, noted that
exposed study subjects also reported this condition approximately 50% more often than either
the unexposed controls or individuals without chloracne (Moses et al., 1984; Suskind and
Hertzberg, 1984). Endocrine studies or reviews of conditions or situations which may lead to
a reduction in libido were not conducted.
The NIOSH and Ranch Hand Studies examined thyroid function based on laboratory
assays. In the 1987 follow-up study, Ranch Hands in the high current dioxin category
experienced significantly decreased mean T3% uptake and increased mean thyroid stimulatory
hormone (TSH) (Wolfe et al., 1991). The authors conclude that there were minor clinically
insignificant differences in mean T3% uptake and mean TSH between the high exposure
group and low exposure group and that TCDD level was not related to an increase in the
prevalence of abnormal levels.
In the NIOSH study, in linear regression analyses serum TCDD was positively and
significantly related to serum levels of luteinizing hormone (LH) and follicle-stimulating
hormone and inversely related to total testosterone after adjustment for potential confounders
(p<05) (Egeland et al., 1992). The prevalence of abnormally low testosterone was two to
three times higher among workers with serum TCDD levels of 20-75 ppt (11.7%, OR=3.9,
95% CI=1.3, 11.3), 76-243 ppt (9.7%, OR = 2.7 CI=0.9, 8.2) or >244 ppt (16.4%, OR = 2.1
95% C.L=0.8, 5.8), than among unexposed referents (4.8%) (mean serum TCDD=7 ppt).
Workers in these same serum TCDD quartiles had a higher prevalence of abnormally high LH
and workers with serum TCDD levels >244 ppt but the differences between each serum
TCDD category and referents were not significant. Further analysis is currently underway.
Evaluation of the prevalence of diabetes and increased fasting serum glucose in the NIOSH
and Ranch Hand Studies as a result of one case report of 55 TCP workers followed over 10
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years noted that approximately 50% of the subjects had either confirmed cases of diabetes or
abnormal glucose tolerance tests (Pazderova-Vejlupkova, 1981). Earlier studies of other
groups exposed to TCDD contaminated chemicals (Suskind and Hertzberg, 1984; Moses et
al., 1984; Webb et al., 1989) found little evidence of an increased risk of diabetes or glucose
intolerance. However, results form the NIOSH (Sweeney et al., 1992) and Ranch Hand
studies (Michalek et al., 1992) suggest that serum TCDD levels may be positively and
significantly related to diabetes and fasting serum glucose levels.
In the NIOSH study, based on logistic regression, the risk of diabetes was found to
increase by approximately 12 percent for every 100 ppt TCDD (p<0.001). Case of diabetes
was defined as reporting a physician diagnosis of diabetes or having a fasting serum glucose
level of 140 mg/dl or higher on 2 occasions. Fasting serum glucose level was 10 percent
higher in workers with 1000 ppt TCD than those with 20 ppt (p<0.001). However, for both
diabetes and fasting serum glucose levels, age and body mass index (kg/m2), both known risk
factors for diabetes, appear to have substantial, and perhaps greater influence on the risk of
diabetes.
In the Ranch Hand study, diabetes was defined as having a history of diabetes or an
oral glucose tolerance test of >200 mg/dl. Risk of diabetes was statistically significantly
increased in Ranch Hand Personnel (RR = 1.5, p<.001) using TCDD categories as an
indicator of exposure. Similarly, serum TCDD was significantly and positively related to
levels of fasting serum glucose levels (Wolfe et al, 1992).
IMMUNOLOGIC EFFECTS
Although animal toxicologic evidence demonstrates adverse immunologic effects after
exposure to 2,3,7,8-TCDD, in humans, there is little information with which to assess the
immunologic consequences of exposure (Table 1).
An immunologic assessment was conducted on 18 British workers 17 years after
accidental industrial exposure to chemicals contaminated with 2,3,7,8-TCDD (Jennings et al.,
1988). There were no significant difference in the levels of immunoglobulins G, A, M, D
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and E, in the number of T and B lymphocytes, in the responsiveness to phytohemagglutinin
A, and in the number of helper and suppressor T cell counts in peripheral blood between
exposed workers and unexposed controls matched for age, race, sex, smoking habit, alcohol
consumption and percent of ideal body weight. Three measures were found to be statistically
significantly (p<.05) higher in workers than in controls: antinuclear antibodies (ANA) (8
workers vs 0 controls p<.01) (when Hep2 cells were used as substrate but not when rat liver
cells were used), immune complexes (workers = 11 vs 3 controls p<.05) and natural killer
cells (NK) (workers = 0.21 x 106/1 vs controls = 0.59 x 106/1 p<002) identified by the
monoclonal antibody Leu-7. No other well conducted studies of exposed individuals have
measured these parameters. In the discussion, the authors could not justify their findings
physiologically and suggested that further research was needed.
Immunologic function among Ranch Handers in the baseline study measured by
analysis of lymphocyte surface markers, total lymphocytes and functional studies using
antigenic (tetanus toxoid) or mitogen (phytohemagglutinin, concavalin A, and pokeweed) did
not differ from that of the unexposed comparison group (Lathrop et al., 1984). Immunologic
evaluation in the first follow-up study was the same as that in the baseline study with the
addition of skin testing with Candida, mumps, trichophyton, Staph-phage-lysate (Lathrop et
al., 1987). Differences were observed between Ranch Handers and the matched comparison
group for abnormal reactions and the delayed hypersensitivity response. Analysis by serum
TCDD level did not confirm that the difference was exposure-related (Wolfe et al., 1991).
The follow-up study found profound effects for the comprehensive cell surface marker and
functional stimulation studies due to smoking, increasing age and alcohol use but not
exposure (Lathrop et al., 1987).
Levels of IgA were positively associated with initial dioxin levels. Other
immunoglobulins IgG and IgM were not significantly related to any serum TCDD level
(Wolfe et al., 1991). The authors suggested that the rise in IgA is consistent with a
subclinical inflammatory response.
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A statistically significant increase in anergy (inability to respond to a challenge by
common antigens) was reported among residents of a trailer park in Missouri which was
sprayed with contaminated 2,3,7,8-TCDD waste oil (Hoffman et al., 1986). However,
corroborating results from in vitro assays of immunologic function did not support the
conclusion that the subjects were anergic. Upon reexamination of only those individuals who
were anergic in the first study, the results of the first study were determined to be invalid.
All of the retested subjects reacted normally to the antigen challenge (Evans et al.> 1987).
Irnmunoglobulin levels measured in Seveso residents exposed to 2,3,7,8-TCDD were
similar to unexposed controls (Reggiani, 1978). In the same study, exposed children from
Seveso also had normal percentages of T and B lymphocytes and normal responses to
mitogens (Table 2).
NEUROLOGIC EFFECTS
Peripheral Nervous System
Although there are no studies reporting neurologic abnormalities related to
2,3,7,8-TCDD exposure in adult animal models, neurological effects are reported to have ,
occurred shortly after exposure in occupationally exposed individuals (Ashe and Suskind,
1950; Baader and Bauer, 1951; Bauer et al., 1961; Goldman, 1973; Jirasek et al., 1974;
Oliver, 1975; Pocchiari et al., 1979) (Table 1) and in Seveso residents (Filippini et al., 1981)
(Table 2).
Among worker populations, symptoms and conditions reported immediately after
exposure include fatigue (Ashe and Suskind, 1950; Suskind et al., 1953; Kimmig and Schulz,
1957; Bauer et al., 1961; Goldman, 1973; Jirasek et al., 1974), pain (Ashe and Suskind, 1950;
Baader and Bauer, 1951; Jirasek et al., 1974; Oliver, 1975), weakness (Baader and Bauer,
1951; Bauer et al., 1961) or reduction in muscle coordination in upper and lower extremities
(Ashe and Suskind, 1950; Baader and Bauer, 1951; Bauer et al., 1961; Goldman, 1973;
Jirasek et al., 1974; Oliver, 1975; Poland et al., 1971), absence (Ashe and Suskind, 1950),
reduction, or alteration in sensory function (Baader and Bauer, 1951; Bauer et al., 1961;
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Goldman, 1973) or motor function (Goldman, 1973; Oliver, 1975), decreased deep tendon
reflex (Kimrnig and Schulz, 1957; Poland et al., 1971), hyperactive deep tendon reflex (Ashe
and Suskind, 1950; Goldman, 1973) and degeneration of distal axons (Ashe and Suskind,
1950). Several authors also observed altered sense of taste (Goldman, 1973; Oliver, 1975),
hearing loss (Goldman, 1973; Kimmig and Schulz, 1957; Poland et al., 1971) and smell
(Goldman, 1973; Poland et al., 1971). Two individuals reported changes in the visual field;
however, there is no clinical evidence to support this information (Oliver, 1975).
A few reports indicate that signs and symptoms of peripheral nerve diseases may
persist in some exposed individuals and may last for as long as 25 years post-exposure
(Suskind et al., 1953; Poland et al., 1971; Moses et al., 1984). Other reports suggest that
symptoms may resolve over time (Jirasek et al., 1974; Pazderova-Vejlupkova et al., 1981).
In 1949, a trichlorophenol reactor release occurred in a plant in Nitro, West Virginia.
In a study conducted in 1979 of volunteers employed at the time of the reactor release, Moses
found a statistically significant (p < 0.01) reduction in sensory function measured by
sensitivity to pinprick among workers with current cases of chloracne (Moses et al., 1984).
This group also included one individual involved in the cleanup of the 1949 accident, who
presented with absent deep tendon reflexes of the lower limb, accompanied by reduced
sensation to pain and vibration and motor weakness. Another study of TCP workers from the
plant in West Virginia conducted in 1979 found no significant changes in the nerve
conduction velocities of the sural and peroneal nerves (Suskind and Hertzberg, 1984).
The relationship between serum 2,3,7,8-TCDD levels and peripheral neuropathy and
neurobehavioral function was examined in a cross-sectional study of U.S. chemical workers
employed in the production of TCP and NTCP or TCP and hexachlorophene and a group of
unexposed referents (Sweeney et al., 1992). Peripheral nerve function was assessed by
electrophysiologic tests of nerve conduction velocity, amplitude and latency, vibratory thermal
threshold, and physical examinations. Neurobehavioral tests measured cognitive function,
mood, memory, and motor skills. Although the workers had substantial exposure to 2,3,7,8-
TCDD (mean lipid-adjusted serum TCDD level = 220 ppt, range to 3,300 ppt) compared with
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the unexposed referent group (mean lipid-adjusted serum, TCDD level = 7 ppt, range to 20
ppt), no differences in peripheral nerve function were detected. Similarly, workers were
similar to referents in the prevalence of mood disorders (Alderfer et al., 1992). Additional
analysis of other neurobehavioral effects in this study population are forthcoming.
In the 1977 screening, 6.7% of the tested residents from Zone A and 1.2% of the
residents in Zone B+R exhibited evidence of clinical neurological damage; and 3.1% of the
Zone A residents and 1.2% of the Zone B+R residents exhibited subclinical neurologic
damage as demonstrated by nerve conduction velocity. No data were provided to support the
reported findings. In 1978, 205 Zone A residents were screened; no residents from Zone
B+R were screened. The proportion of individuals with clinical neurologic damage in Zone
A residents increased to 11.7% and the proportion of subclinical findings increased to 4.9% of
the group.
In 1981, Filippini published a cross-sectional study of a total of 308 Seveso residents
who participated in all parts of the 1978 neurologic screening program sponsored by the
Italian Government (Filippini et al., 1981). Prevalence risk ratios (PRR) for peripheral
neuropathy were determined separately for all Seveso residents and for those who exhibited
clinical indication of 2,3,7,8-TCDD exposure, defined as the presence of elevated liver
enzyme levels (GOT, SGOT, SGPT) (which are also indicative of nonspecific insults to the
liver), or chloracne. PRRs for peripheral neuropathy were also determined for residents
exhibiting conditions that are risk factors for neuropathy, e.g., alcoholism, inflammatory
disease, diabetes, or potential occupational exposure to neurotoxins, etc. Filippini found that
Seveso residents who had clinical indication of TCDD exposure (chloracne, or elevated liver
enzymes GOT, AST, ALT) or who had risk factors for neuropathy were found to have
significantly greater prevalence of peripheral neuropathy than residents without either
manifestation (Prevalence Risk Ratios (PRR) exposure = 2.8, 95% CI=1.2-6.5; PRR (possible
TCDD-predisposing factors) = 2.6%, 95% CI=1.2-5.6) (Filippini et al., 1981). Additional
analysis identified further that individuals who met the definition for chloracne or abnormal
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levels of hepatic enzymes were significantly more at risk than residents without either
condition.
Residents of Seveso who developed chlorance after the reactor release (N = 193) were
invited to a series of three follow-up screenings in 1982-1983, 1983-1984 and in 1985. A
control group from a nearby but uncontaminated area were also examined. No increases in
the prevalence of abnormal electrophysoilogic measures were observed in the Seveso group
(Assennato et al, 1989).
Unlike the findings among Seveso residents, no neurological or other abnormalities
were found in a self-selected group of Missouri residents who lived in communities at the
time the areas were sprayed with 2,3,7,8-TCDD contaminated waste oil (Webb et al., 1987).
In this study, high risk of TCDD exposure was defined as "potential exposure to between 20
and 100 parts per billion (ppb) of TCDD for at least 2 years or levels greater than 100 ppb
for at least 6 months." Low risk of exposure included individuals with little or no reported
exposure to 2,3,7,8-TCDD. In a second study, no health effects related to exposure to
2,3,7,8-TCDD-contaminated wastes were noted in residents with adipose tissue levels ranging
from 3.7 ppt to 750 ppt (Webb et al., 1989).
The first of the examination series published in 1984 (baseline) included a
comprehensive neurologic assessment and electrophysiologic tests (Lathrop et al., 1984). In
the second and third examination (followup), the nerve conduction velocities were omitted
(Lathrop et al., 1987; Wolfe et al., 1991). The results of both the baseline and followup
exams showed little or no difference between the Ranch Hand group and their controls, or
within the six exposure groups. With the exception of a statistically significantly increase in
abnormal Babinski reflex among Ranch Hand personnel in the baseline study only, no other
outcomes differed between Ranch Handers and controls in either study. In the 1987 followup
study there was a significantly increased risk of coordination abnormalities in Ranch Hands
with current levels of serum 2,3,7,8-TCDD above 33.3 ppt (Wolfe et al., 1991).
Reports of workers exposed to 2,3,7,8-TCDD-contaminated chemicals have also noted
symptoms reflecting central nervous system (CNS) involvement. These include decreased
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coordination (Oliver, 1975), headaches (Ashe and Suskind, 195O; Bauer et al., 1961; Jirasek
et al., 1974; Poland et al., 1971; Oliver, 1975), nervousness (Ashe and Suskind, 1950;
Suskind et al., 1953), sleeping disturbances (Bauer et al,, 1961; Oliver, 1975),, mood changes
(Oliver, 1975), loss of concentration (Oliver, 1975), depression (Bauer et al., 1961), abnormal
EEG (Bauer et al., 1961; Jirasek et al., 1974) and suggestions of hypomania as indicated by
scores of a personality inventory (Poland et al., 1971).
RESPIRATORY AND CARDIOVASCULAR EFFECTS
Respiratory Effects
Adverse outcomes of the respiratory system associated with 2,3,7,8-TCDD exposure
are varied and inconsistent among exposed populations. Effects include acute bronchitis-like
symptoms and hemorrhagic pleurisy in German TCP workers (Goldman, 1973) and reduced
overall pulmonary function in West Virginian TCP workers (Suskind et al., 1953; Suskind
and Hertzberg, 1984) (Table 51). A cross-sectional medical assessment of West Virginia TCP
production workers found a statistically significant increase in the percent of abnormal
findings among workers who smoked at the time of the examination compared to unexposed
smokers for forced expiratory volume (FEV) (exposed = 27% abnormals vs unexposed =
4.4% abnormals), forced vital capacity (FVC), (exposed 25.7% abnormals vs unexposed 2.2%
abnormals), forced expiratory volume in one second (FEV1)/FVC ratio (exposed = 25.7%
abnormals vs unexposed = 7.7% abnormals) and forced midexpiratory flow rate (FEF25-75)
(exposed = 36.5% abnormals vs unexposed =11.1% abnormals) (Suskind and Hertzberg,
1984). This trend remained when pack-years of smoking was taken into account. In contrast,
differences between exposed and unexposed were not observed in workers who never smoked
or in former smokers. In a study of New Jersey TCP workers Poland et al. (1971) identified
18 workers with impaired "diaphramatic excursion", 14 or 77% of whom were smokers at the
time of the examination and three were former smokers. Serum dioxin levels (initial and
current dioxin) were significantly associated with FVC, FEV1-0 and FEF max and FEVLO/FVC
among Ranch Hand personnel (Wolfe et al., 1991). However, the authors indicate that the
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differences in the mean levels were not clinically important. The authors suggest that further
analyses considering percent body fat may assist in the interpretation of these results.
Other morbidity studies, including the NIOSH study, or case series have hot found or
reported these or other types of respiratory system impairment in exposed populations (Moses
et aL, 1984; Jirasek et al., 1974; Pazderova-Vejlupkova et al., 1981; Lathrop et al., 1984;
Lathrop et al., 1987; Calvert el al., 1991). Furthermore, deficits in the proportionate mortality
from non-malignant respiratory diseases were found among West Virginian 2,4,5-T workers
(observed = 2 vs expected = 2.67) (Zack and Gaffey, 1983) and the standardized mortality of
Michigan TCP and chlorophenol production workers (Ott et al., 1987) from diseases of the
respiratory system (observed = 16 vs expected = 21.2).
Cardiovascular Effects
Two studies found evidence of cardiovascular disease related to exposure to
2,3,7,8-TCDD contaminated chemicals. In the first of the Air Force Ranch Hand Health
Studies, Ranch Handers had significantly reduced peripheral pulses when measured using a
manual procedure (Lathrop et al., 1984) and greater mean corpuscular volume and corpuscular
hemoglobin volume. In the first follow-up study conducted in 1985, these effects
disappeared. The reversal in the results of the peripheral pulse was attributed to a change to
a more objective measuring method, a Doppler procedure, and to the prohibition of smoking
for four hours prior to the test (Lathrop et al., 1987). Analysis by serum TCDD level
category appear to contrdict the findings by Lathrop et al. (1987))(Wolfe et al, 1991). Ranch
Hands in the high current dioxin category had significantly more peripheral pulse
abnormalities than the comparison group. The comparisons had a median serum TCDD level
of 4.2 ppt (range 0-55 ppt). In addition, Ranch Hands in the same group had a significant
increase in essential hypertension compared to the comparison group.
In the baseline study, no difference was observed in the rate of heart disease among
Ranch Handers or their comparisons (Lathrop et al, 1984). In the first follow-up study,
however, Ranch Handers reported significantly more confirmed heart disease than in the
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comparison group (RR = 1.22, 95% CI = 1.00, 1.50), although the finding did not consistently
correlate with 26 other clinical measures of cardiovascular function (Lathrop et al, 1987).
Analysis by serum TCDD level of the 1987 data suggests that there is no evidence for
increased incidence of cardivascular disease with comparisons appearing to be at higher risk
than their exposed counterparts (Wolfe et al, 1991). Studies of workers from the West
Virginia plant found no relationship between history of coronary artery disease (Suskind and
Hertzberg, 1984), angina (Suskind and Hertzberg, 1984; Moses et al., 1984) and myocardial
infarction (Moses et al., 1984) and employment in TCP production or presence of chloracne
(Moses et al., 1984). Pazderova-Vejlupkova (1981) described a fatal case of unusually severe
atherosclerosis in a 57-year-old worker identified as having a "severe type of TCDD
intoxication." History of hyperlipidemia or the presence of other risk factors was not
described.
Statistically nonsignificant increases in proportional mortality from atherosclerotic
heart disease were found among 2,4,5-T workers employed at the West Virginia plant
(observed = 27 vs expected= 19.72; PMR=117) (Zack and Gaffey, 1983). The proportional
mortality for other diseases of the circulatory system was decreased (observed = 4 vs
expected 6.76; PMR=59). Mortality studies of other cohorts of TCP workers found no
elevation in mortality from cardiovascular disease among employees at the BASF plant in
Ludwigshafen (Theiss et al., 1982) or among workers employed in the production of
chlorophenols at the Dow Chemical Company in Midland, Michigan (Ott et al., 1987; Bond et
al., 1989). The discrepancies observed among these studies may be due to the differences in
the study designs and demographics of the study populations, and the selection of the
comparison group.
RENAL EFFECTS
There is little evidence in the animal or human data to suggest that exposure to
2,3,7,8-TCDD is related to renal or bladder dysfunction. In a single case report, a child
exposed to 2,3,7,8-TCDD after contact with soil sprayed with contaminated waste oil was
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diagnosed with focal pyelonephritis (Kimbrough et al., 1977) (Table 1). After diagnosis and
treatment, the condition resolved with no reported recurrence. No major renal or bladder
dysfunctions were noted among Air Force Ranch Handers (Lathrop et al., 1984; Lathrop et
al., 1987; Wolfe et al., 1991) or among TCP workers from West Virginia (Suskind and
Hertzberg, 1984) or from New Jersey (Poland et al., 1971).
REPRODUCTIVE EFFECTS
The results of human studies designed to examine the reproductive effects of
2,3,7,8-TCDD contaminated chemicals have not produced convincing evidence to support the
animal data. In animals, exposure to 2,3,7,8-TCDD has been associated with excesses of
birth defects (Moore et al., 1973), fetal loss (Courtney, 1976) and reduced fertility (Giavini et
al., 1983). In general, the human studies suffer from several limitations: insufficient power to
detect relatively rare events, inadequate information on maternal and paternal exposure to
2,3,7,8-TCDD contaminated chemicals, possible incomplete ascertainment of reproductive
• events and incomplete ascertainment of confounders.
Two studies of occupational groups, U.S. chemical workers exposed to TCP, 2,4,5-T
or pentachlorophenol (Townsend et al., 1982) and New Zealand 2,4,5-T sprayers (Smith et al.,
1982) found no overall statistically significant association between exposure and adverse
reproductive events such as congenital defects or miscarriages (Table 4).
Among potentially exposed community residents a study of the frequency of birth
defects occurring in the Seveso population between 1977 and 1982 and reported to the Seveso
Congenital Malformations Registry found no difference in the rate of birth defects or
stillbirths in the exposed population when compared to residents from unexposed regions
(Mastroiacovo et al., 1988). As described by the authors, the major limitations of this study
included a small sample size (N=15,291 births), possible misclassification of exposure and the
exclusion of spontaneous abortions which may have been due to fetal malformations. Among
mothers with addresses in contaminated areas of Missouri no significant excesses were noted
for total birth defects, fetal deaths or low birth weight (Stockbaure et al., 1988).
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In a study of 8,263 conceptions and 6,792 live births among 872 Ranch Hands and
1206 Comparisons, few significant associations were found between serum TCDD levels and
adverse reproductive outcomes (Wolfe et al., 1992). The analyses evaluated the relationship
between TCDD level and miscarriages, tubal pregnancies, stillbirth, low birth weight, neonatal
mortality, major birth defects or severity of birth defects. No associations were found
between father's TCDD level and sperm count and the percentage of abnormal sperm. These
data were based on serum TCDD levels collected in 1987 and semun collected in 1982 during
the baseline examination.
MORTALITY FROM CAUSES OTHER THAN CANCER
Mortality from nonmalignant causes of death has been reported most often for the
classification "external causes of death" which includes deaths due to accidents, homicide, and
suicide (Table 5). These causes of death could be important because excesses may reflect
changes in mood and behavior reported in earlier studies and case reports of exposed workers
(Suskind, 1953; Poland et al., 1971). In a cohort mortality study of a small number of
forestry workers employed in Canada and who may have been exposed to 2,4-D and 2,4,5-T,
deaths due to suicide were significantly elevated among individuals employed less than 14
years in the industry between 1950-1982 (11 observed vs 5.2 expected, 95% CI=l26-298).
Other factors which may have lead to suicide were not considered in this analysis.
ADD: RH MORTALITY STUDY; NIOSH MORTALITY (NONCANCER-MORTALITY)
HERE
OVERALL SUMMARY OF HUMAN HEALTH EFFECTS
Although there is considerable literature reporting the effects of human exposure to
2,3,7,8-TCDD contaminated materials, the data do not describe one condition or a series of
long-term health effects which are consistent among every exposed population. Results of
clinical cross-sectional studies provide the most consistent information, suggesting that some
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effects are transient, particularly increased liver enzyme levels and urinary porphyrins, and
that other effects may persist in some individuals, particularly chloracne, and elevated lipid
levels. However, these data are unable to determine the characteristics which distinguish
individuals with persistent effects from those without.
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7-103
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DRAFT-DO NOT QUOTE OR CITE
Dioxin Analysis of 1987 Examination Results. Epidemiology Research Division, Armstrong
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7-104
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DRAFT-DO NOT QUOTE OR CITE
TABLE 1. SUMMARY OF HEALTH EFFECTS IN CHEMICAL WORKERS EXPOSED TO
2,3,7,8-TCDD-CONTAMINATED MATERIALS
Ash
1950
Exposure TCP
Dermatologic
Chloracne +
Other +1A3
Hepatic
Size increase +
PCT
Enzyme rise
Other +S-B
Gastrointestinal
Ulcers +
Lipid rise NR
Other +7
Pulmonary +
Cardiac NR
Neurologic +
Other effects V
Badder Kimmig Bauer
1951 1957 , 1961
TCP TCP TCP
PCP 2,4,5-P 2,4,5-T
.
'
NR NR NR
NR NR NR
NR NR NR
NR NR +6
NR NR NR
NR NR NR
+7 NR +7
+ NR NR
+ NR NR
.*•
+8 +B +8
Bleiberg
1964
TCP
2,4,5-T
+
NR
+4
+s
NR
NR
NR
NR
NR
NR
NR
NR
1Hyperplgmentatlon or hlrsutlsm
2Cysts on eyelids, blepharitis, or conjuctlvitls
3SkIn fragility
4UroporphyrIns
5ALT and/or AST
'Hepatitis (not specified)
7Right upper quadrant pain
"Reduced libido
+=PosItive finding reported in exposed group
-=Negative finding reported in exposed group
NR=not reported
TCP=trichlorophenol
2,4,5-T=2,4,5-trichlorophenoxyaceticacid
7-105
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DRAFT-DO NOT QUOTE OR CITE
TABLE 1 (continued)
Exposure
Dermatologle
Chloracne
Other
Hepatic
Size increase
PCT
Enzyme rise
Other
Gastrointestinal
Ulcers
Llpid rise
Other
Pulmonary
Cardiac
Neurologic
Other effects
— Poland
1971
TCP
2,4,5-T
+
+1.2
N
+«
+11
NR
NR
NR
NR
NR
NR
+
NR
Goldman
1973
TCP
+
NR
NR
+
NR
+6
NR
NR
NR
NR
+
*'
NR
— May
1973
TCP
2,4,5-T
+
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Oliver
1975
Pure
2,3,7,8-
TCDD
+
+1
NR
NR
NR
NR
NR
+
+
NR
NR
+
NR
Jlrasek
1974
TCP
2,4,5-T, PCP
+
+1
NR
+4'9
+5,12,13
NR
NR
+
+7
NR
NR
+
+14
1HyperpIgmentatIon or hlrsutism
sCysts on eyelids, blepharitis, or conjunctivitis
4Uroporphyrlns
•ALT and/or AST
'Hepatitis (not specified)
7RIght upper quadrant pain
9UV fluorescence of liver
"LDH
WALK
"Delta-ALA
"Diabetes or abnormal glucose tolerance test
+=Positive finding reported in exposed group
-=Negatlve finding reported in exposed group
NR=not reported
TCP=trichlorophenol
2,4,5-T=2,4,5-trichIorophenoxyaceticacid
7-106
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DRAFTS-DO NOT QUOTE OR CITE
TABLE 1 (continued)
Exposure
Dermatologic
Chloracne
Other
Hepatic
Size increase
PCT
Enzyme rise
Other
Gastrointestinal
Ulcers
Lipid rise
Other
Pulmonary
Cardiac
Neurologic
Other effects
Pazderova
1981
TCP
2,4,5-T
+
NR
NR
NR
NR
NR
NR
+
NR
NR
NR
+
+14
Martin May
1982 1983
TCP TCP
2,4,5-T 2,4,5-T
+ +
NR NR
NR
NR -15-17
+1S +s
NR
NR - •
+ -
NR
NR -
NR -
NR NR
NR -
Van Houdt
1983
2,4,5-T
NR
NR
NR
a
.5,15
NR
NR
NR
NR
+
NR
NR
Bond
1983
TCP
2,4,5-T
NR
NR
NR
NR
NR
NR
+
+
NR
NR
NR
NR
SALT and/or AST
"Diabetes or abnormal glucose tolerance test
1SGGT
17D-glucaric acid
+=Positive finding reported in exposed group
-=Negative finding reported in exposed group
NR=not reported
TCP=trichlorophenol
2,4,5-T=2,4,5-trichlorophenoxyacetic acid
7-107
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DRAFT-DO NOT QUOTE OR CITE
TABLE 1 (continued)
Exposure
Dermatologlc
Chloracne
Other
Hepatic
Size Increase
PCT
Enzyme rise
Other
Gastrointestinal
Ulcers
LIpid rise
Other
Pulmonary
Cardiac
Neurologic
Other effects
Martin
1984
TCP
2,4,5-T
+
NR
NR
NR
+1S,17
NR
NR
+
NR
NR
NR
NR
NR
Suskind Moses
1984 1984
TCP TCP
2,4,5-T 2,4,5-T
+ +
+16 +16
NR
NR
+1S
NR
+ NR
+ +
NR NR
+ NR
+ NR
+
+8 +"
Jennings
1988
TCP
2,4,5-T
NR
+
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
>21
Calvert
1991
TCP
2,4,5-T
NR
NR
NR
NR
NR
NR
NR
NR
NR
-
NR
NR
NR
'Reduced libido
"GGT
"Actinic changes
17D-gIucarlc acid
"Increased Immune complex
+=PosItive finding reported In exposed group
-=Negative finding reported In exposed group
NR=not reported
TCP=trlchlorophenol
7-108
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DRAFT-DO NOT QUOTE OR CITE
TABLE 1 (continued)
Exposure
Dermatologic
Chloracne
Other
Hepatic
Size increase
PCT
Enzyme rise
Other
Gastrointestinal
Ulcers
Lipid rise
Other
Pulmonary
Cardiac
Neurologic
Other effects
Calvert
1992
TCP
2,4,5-T
NR
NR
.
NR
+15'
NR
.
NR
•
NR
NR
NR
NR
Sweeney ~ ~~ ' •
1992
TCP
2,4,5-T
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
-
NR
15°Only among heavy drinkers
+=Positlve finding reported In exposed group
-^Negative finding reported in exposed group
NR=not reported
TCP=trIchlorophenol
2,4,5-T=trichlorophenoxyaceticacid
7-109
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DRAFT-DO NOT QUOTE OR CITE
TABLE 2. SUMMARY OF HEALTH EFFECTS AMONG RESIDENTS OF SEVESO, ITALY, AND
Study Type
Dermatologlc
Chloracne
Other
Hepatic
Size Increase
PCT
Enzyme rise
Other
Gastrointestinal
Ulcers
Lipld rise
Other
Pulmonary
Cardiac
Neurologic
Other effects
Reggianl
1980
Case
Report
:«
NR
+15
NR
NR
NR
NR
NR
-
NR
Fillpplnl
1981
Cross-
Sectional
NR
NR
NR
NR
NR
NR
NR
NR
NR
* .
*
NR
Assennato
1989
Cross-
Sectional
:
NR
NR
NR
NR
NR
NR
+19
-
NR
Ideo
1985
Cross-
Sectional
NR
NR
NR
NR
+17
NR
NR
NR
NR
NR
NR
NR
NR
Mocarelli
1986
Cross-
Sectional
NR
NR
NR
NR
+5,1S
NR
NR
NR
NR
NR
NR
NR
NR
SALT and/or AST
"GGT
"D-glucarlc acid
"Heart disease
"Blisters and burn-like lesions
+=Positive finding reported in exposed group
-=Negative finding reported in exposed group
NR=not reported
TCP=trichlorophenol
7-110
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DRAFT-DO NOT QUOTE OR CITE
TABLE 2 (continued)
4Uroporphyrins
SALT and/or AST
17D-glucarIc acid
2EAnergic responses
Klmbrough Steinberg Hoffman Webb
1977 1985 1986 1989
Study Type
Dermatologic
Chloracne
Other
Hepatic
Size increase
PCT
Enzyme rise
Other
Gastrointestinal -
Ulcers
Lipid rise
Other
Pulmonary
Cardiac
Neurologic
Other effects
Case
Report
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
+4
Cross- Cross- Cross-
Sectional Sectional Sectional
NR - .
NR .
NR - .
NR +4 .
.5,17
NR •
NR
NR
NR - .
ji
NR - .
NR . .
NR
NR +=»
+=Positive finding reported In exposed group
-=NegatIve finding reported in exposed group
NR=not reported
TCP=trichlorophenol
7-111
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DRAFT-DO NOT QUOTE OR CITE
TABLE 3. SUMMARY OF HEALTH EFFECTS AMONG U.S. AIR FORCE RANCH HAND
PERSONNEL _
WoUe
Lathrop
1984
Lathrop
1987
1991
Exposure
2,4,5-T
2,4,5-T
Agent Orange (2,4,5-T)
Dermatologlc
Chloracne
Other
.18
.18
Hepatic
Size increase
PCT
Enzyme rise
Other
_15,11
+
,15,23
Gastrointestinal
Ulcers
Llpld rise
Other
.27
Pulmonary
.36
Cardiac
.28,29
Neurologic
.26
Other effects
.20
.30,31,32,33,34,35
11LDH
1SGGT
"Basal cell carcinoma
"Heart diseases
"Hemoglobin volume
"ALT
"Coordination abnormalities
"Cholesterol, HDL, choIesterol-HDL ratio
"Systolic blood pressure
"Peripheral pulse abnormalities
*>tWBC
3tiT.,% uptake
321TSH
334Testicular size
34tDiabetes
3SUgA
^IFEV^ FVC, FEV^FVC, FEFma
+=Positive finding reported in exposed group
-=Negative finding reported in exposed group
NR=not reported
TCPstrlchlorophenol
2,4,5-T=trlchlorophenoxyacetic acid
7-112
9/10/92
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