• Home
• About ATSDR
• Press Room
• A-Z Index
• Employment
• Contact Us
• CDC

Comparison Of Dioxin Subregistry Baseline

SECTION 1

INTRODUCTION

This is a report on the Baseline, Followup 1, and Followup 2 activities and findings from the analyses of data collected from participants in the Dioxin Subregistry. The Dioxin Subregistry is part of the National Exposure Registry, which was created and is being maintained by the Agency for Toxic Substances and Disease Registry (ATSDR).

In 1988, the policies and procedures proposed for the National Exposure Registry were reviewed extensively by several committees of independent scientists, state representatives, representatives of other federal agencies, and other interested people. The policies and procedures were published in the National Exposure Registry Policies and Procedures Manual (1) and were revised in 1994 (2). The Dioxin Subregistry was one of the first subregistries to be established as part of the National Exposure Registry program. There are currently three chemical subregistries (trichloroethylene, benzene, and dioxin). Two additional subregistries (chromium and radioactive substances) are planned.

In keeping with Registry goals (1), this report represents the first of a set of ongoing reports and publications that will summarize the latest Dioxin Subregistry findings and suggest specific hypotheses for future research. The research will focus on these and other residential populations that have experienced similar exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin, hereafter referred to as“dioxin”. This report highlights some health outcomes and confounding variables that should be considered for analysis in future epidemiological or health studies.

The Policies and Procedures Manual (1) describes in detail all policies, procedures, and operational details pertinent to establishing the dioxin and other subregistries of the National Exposure Registry. Specific topics from the policies and procedures document are reiterated in this report, where necessary, for clarity.

Section 2 of the report provides a discussion of the information available in 1988, the year the Dioxin Subregistry was approved, on the toxicity of dioxin-the related epidemiological and toxicological studies. Section 3 presents a detailed discussion of the sites included in the Dioxin Subregistry, including information on residential sampling schemes and periods of exposure. Section 3 also provides descriptive and summary information on the environmental data and a description of the previous health studies in the Times Beach, Missouri, area. A discussion by site of the data collection period, participation rates, and number of registrants is included.

Section 4 of this report provides an overview of the characteristics and health status of registrants who took part in the Baseline effort. Section 4 also includes the comparison of the Dioxin Subregistry data with national survey data files for smoking habits and demographic characteristics and reporting rates of adverse health outcomes. Section 5 provides the same information for Followup 1 and Followup 2. Section 6 summarizes the findings of the report and discusses the findings in relationship to the published literature. Section 7 states the conclusions of the analysis of the Dioxin Subregistry Baseline data and outlines the future activities related to the subregistry.

SECTION 2

THE INCLUSION OF DIOXIN AS A PRIMARY CONTAMINANT

BACKGROUND

In the early 1970s, approximately 29 kilograms of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin)-contaminated sludge wastes, originating as by-products of hexachlorophene production in a southwest Missouri plant, were mixed with waste oils and sprayed for dust control throughout the state. As of 1987, almost 250 residential, recreational (including several horse arenas), and commercial areas were thought to be contaminated; 44 sites had been confirmed as having at least 1 part per billion (ppb) of dioxin in the soil (3). At one of these sites, levels as high as 33,000 ppb were measured. Isolated levels of more than 2,000 ppb were found in some contaminated areas, but most detectable levels in soil samples ranged from several hundred parts per billion to less than 1 ppb.

In August of 1971, the Centers for Disease Control (CDC) and the Missouri Department of Health (MDH) became involved in the investigation of this contamination after receiving a report of a child who had developed hemorrhagic cystitis (4) after playing in an oil-treated horse arena. In 1974, this work culminated in the laboratory identification of dioxin in the waste oil and soil. With the discovery of widespread dioxin contamination in Missouri in mid-1982, CDC, in consultation with the MDH, resumed public health activities.

By January 1983, the following public health actions had been initiated by CDC and the MDH:

1.Provision of health education for both the medical and public health communities, as well as the general public, about then current understandings of the health effects of dioxin exposure.

2.Provision of a dermatologic screening clinic to the general public.

3.Creation of a central listing of potentially exposed people.

4.Design and implementation of a pilot medical study of a "highest risk" cohort (4).

These activities led to further MDH and CDC studies, including the following:

1.Quail Run Medical Epidemiology Study (1984/5)

2.Quail Run Follow-up Study (1985/6)

3.Reproductive Outcomes Study (1985/6)

4.Adipose (Fat) Tissue Study (1986)

In 1988, the decision was made to include dioxin as a primary chemical for one of the first subregistries of the National Exposure Registry. The factors that led to the selection of dioxin were the documented presence of dioxin in the environment; published evidence of dioxin toxicity in worker populations and in toxicologic studies; the paucity of information on low-level, long-term exposures to dioxin; and the extreme national concern regarding the general health effects of dioxin. It was thought that the Registry could contribute significantly to the information available on the association of adverse health effects, should they exist, following long-term, low-level exposure to dioxin in the environment. The policies and procedures for establishing subregistries are described elsewhere (1,2).

HUMAN DATA

As of 1988, the year the Dioxin Subregistry was established, relatively little was known about the human health effects following exposure to dioxin (Figure 2-1). (Note: In this section, the discussion is limited to the information available in 1988. Information available since that time is included in Section 6). Most of the direct knowledge of the effects of dioxin exposure on human health had been obtained from the study of workers exposed to dioxin during the production or subsequent handling of 2,4,5-trichlorophenol or pesticides produced therefrom, such as 2,4,5-trichlorophenoxyacetic acid (4). Chloracne, immunotoxicity, hyperpigmentation, hyperkeratosis, hirsutism of the skin, possible hepatotoxicity, hypertriglyceridemia and hypercholesterolemia, aching muscles, loss of appetite, weight loss, digestive disorders, headaches, neuropathy, insomnia, sensory changes, and loss of libido had been observed in humans exposed to chemicals contaminated with dioxin (6). These reported effects could have been the result of dioxin exposure, or of exposure to the chemicals of which dioxin is a contaminant or to the solvents in which these compounds are normally dissolved. Because some herbicides and some industrial chemicals contain dioxin as a contaminant, the primary route of exposure was most likely dermal, although some oral and inhalation exposure also occurred.

Chloracne was the only substantiated effect produced in humans by certain compounds contaminated with dioxin. These persistent, deforming lesions of the face and upper body had been recognized for many years as resulting from exposure to certain halogenated aromatic compounds, and it was believed that dioxin was the most effective compound in producing these lesions.

Evidence suggested that dioxin was hepatotoxic in humans. In populations exposed to herbicides and other industrial chemicals contaminated with dioxin, there had been reports of increased serum levels of liver enzymes and the development of porphyria cutanea tarda (PCT), an acquired form of porphyria characterized by chronic skin lesions (6). In all studies, however, exposure could have been to chemicals that can also cause liver damage, and the diagnosis of PCT in some of the studies might have been questionable. Similarly, data suggested that dioxin might affect the immune system in humans, but the same limitations discussed with regard to hepatotoxicity applied to immunotoxicity.

Studies of human populations exposed to herbicides and other industrial chemicals contaminated with dioxin suggested that dioxin produced a variety of developmental effects. After reviewing these studies, the U.S. Environmental Protection Agency (EPA) indicated that the data were not inconsistent with dioxin adversely affecting development, but as a result of the limitations

Figure 2-1.—Availability of information on the health effects of dioxin (human data).



of the data, these studies could not prove an association with dioxin exposure and the observed effect (6). The major limitations in these human studies were the concomitant exposures to other potentially toxic chemicals, the lack of any specific quantitative data on the extent of exposure of individuals within the study group, and the lack of statistical power.

EPA also reviewed human reproductive toxicity studies of groups exposed to herbicides and other industrial chemicals contaminated with dioxin. These studies did not provide a scientifically valid indication that dioxin adversely affected either male or female reproductive performance, or that exposure to dioxin was without effect (6). The limitations of the studies are similar to those discussed previously.

In several epidemiology studies of humans exposed to herbicides contaminated with dioxin (reviewed in 6), an association was reported between exposure and soft tissue sarcomas (of various sites) and lymphomas. Although many of these studies had confounding factors, the problems with the studies were not sufficient to explain the highly significant risks of soft tissue sarcoma in workers. In addition, EPA reviewed a number of studies that were considered to be consistent with or tended to support the findings of soft tissue sarcoma in groups thought to be exposed to chemicals contaminated with dioxin. A number of these studies found no association between risk of soft tissue sarcoma and exposure to herbicides contaminated with dioxin. EPA concluded that the epidemiologic data appeared to provide limited evidence that exposure to phenoxyacetic acid herbicides or chlorophenols, or both, was causally related to the risks of soft tissue sarcoma, but none of the data were sufficient to implicate dioxin alone (6).

Information on the health effects of nonoccupational environmental exposure to dioxin and its congeners was sparse. After an explosion in 1976 at the ICMESA plant in Seveso, Italy, exposed children developed chloracne, the exposed population exhibited abnormal liver function tests, and persons with chloracne showed a statistically significantly elevated incidence of abnormal nerve conduction in tests (6). In 1971, in Missouri, a child developed hemorrhagic cystitis after playing in a riding arena containing dirt contaminated with dioxin in concentrations as high as 33,000 ppb (6).

Published reports presented the results of measurements of dioxin in human tissues. One report described the distribution of dioxin in a 55-year-old woman who was exposed to a mean soil dioxin concentration of 185.4 parts per billion dioxin for 16 days in Seveso, Italy. She died of pancreatic cancer 7 months after the explosion at the ICMESA plant, and post-mortem tissue analysis revealed dioxin levels of 1,840 parts per trillion (ppt) in fat, 150 ppt in liver, 60 ppt in brain, and 6 ppt in blood. No other tissue analyses have been reported from individuals exposed at Seveso (6).

ANIMAL DATA

The amount of animal evidence for the toxicity of dioxin (Figure 2-2), although also limited in 1988, was greater than that for humans. Four major toxic effects characteristic of dioxin are chloracne, the wasting syndrome, hepatotoxicity, and immunotoxicity. As of 1988, the latter three effects had been clearly demonstrated only in laboratory animals.

Since chloracne, the only lesion definitely identified in humans as resulting from dioxin exposure, could be detected in only a few species, the investigation of this effect had been limited. The only dermal animal data that provided quantitative information on chloracne were from a study in which hairless mice treated with dioxin developed dermal lesions that resembled some features of chloracne in humans (6).

The wasting syndrome was characterized by extreme loss of body weight. In acute oral exposure studies, this syndrome was associated with lethal doses. A dose-response relationship for the wasting syndrome had been defined in a 90-day study in guinea pigs (6).

Dioxin was hepatotoxic in all species tested; however, the severity of the lesions depended on the species studied. Although liver damage was not as severe in the guinea pig, the most sensitive species tested with regard to lethality, liver changes such as focal necrosis and hypertrophy had been observed at very low doses. There were studies of chronic exposure in guinea pigs; however, results of studies of chronic exposure in rats showed "toxic hepatitis" and degenerative changes (6).

The guinea pig also appeared to be the species most sensitive to the immunotoxic effects of dioxin. Studies had reported a decrease in thymus weight, total lymphocyte number, and total leukocyte number. Immunologic effects from exposure to dioxin had also been reported in mice (6).

Dioxin produced anomalies in the fetus, including cleft palate and hydronephrotic kidneys in mice and internal organ hemorrhage in the rat. In studies of monkeys exposed to dioxin through diet, spontaneous abortions occurred in two-thirds of the monkeys. Rats fed high doses of dioxin had decreased fetal survival. Medium doses affected litter size and fetal and neonatal survival. The

Figure 2-2.—Availability of information on the health effects of dioxin (animal data).



lowest doses produced dilated renal pelvises, decreased fetal weight, and changes in the gestational index.

Dioxin produced mostly negative results in tests for genotoxicity; however, there were a few positive responses, which suggested that dioxin was genotoxic. Dioxin had been demonstrated to be an animal carcinogen in both rats and mice. In Swiss mice, females, but not males, developed skin tumors following treatment with dioxin. There had also been mixed evidence that dioxin was a tumor promoter.

In summary, at the time the Dioxin Subregistry was established, there was a lack of substantive information on the health effects of dioxin following nonoccupational exposures. The Dioxin Subregistry was created to aid in addressing this data gap.

SECTION 3

POPULATION SELECTION AND SITE DESCRIPTIONS

BACKGROUND

According to Kay (7), in the 1960s Hoffman-Taft in Verona, Missouri, produced a defoliant composed of 2,4-dichlorophenol and 2,4,5-trichlorophenol, which was called "agent orange" by the military due to the identifying color stripe on its container. As a result of curtailed use of the herbicide in Vietnam, the company ceased manufacturing and the facilities sat idle for a number of months. On November 18, 1969, the Northeastern Pharmaceutical and Chemical Company (NEPACCO) leased the manufacturing line to make hexachlorophene, an antiseptic. One of the by-products of this process was 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Shortly thereafter, the entire plant was acquired by Syntex-Agribusiness; however, NEPACCO remained active at the plant until early 1972, when the hexachlorophene market collapsed.

During the period from February 16, 1971, through October 25, 1971, Bliss Waste Oil Service picked up six truckloads of still bottoms from NEPACCO (8). The loads, approximately 3,000 gallons each, were hauled to eastern Missouri (Figure 3-1). Almost all of this material was either sprayed directly or as a mixture with waste oil as a dust suppressant.

SITE DESCRIPTIONS

The participants in the Dioxin Subregistry represent individuals who were potentially exposed to dioxin at one of four sites (Figure 3-2) in Missouri-the Quail Run Mobile Home Park, Minker/Stout/Romaine Creek, Shenandoah Stables, and Times Beach. These sites were quite varied with respect to the type of exposure, as well as the levels of dioxin (Table 3-1). A description of each of these sites follows.

Quail Run Mobile Home Park

In January 1983, the U.S. Environmental Protection Agency (EPA) received information that the central road of the Quail Run Mobile Home Park in Gray Summit, Franklin County, had been sprayed with dioxin-contaminated oil in April 1971. Dioxin, measuring 50 parts per billion (ppb), was discovered in soil samples collected by EPA in March 1983.

Subsequent investigations revealed that the contamination had spread from the road throughout the site via tracking, wind and water erosion, and contaminated soil used as fill at nearby locations. Dioxin was detected along the entire length of the road that runs through the park, with levels ranging from 39 ppb to 1,100 ppb in composite soil samples (2,200 ppb dioxin was measured in a single noncomposite sample). It was measured at levels >1 ppb along both road shoulders, in 4 of 8 yards tested, in dust samples collected from the interiors of 21 of 31 mobile homes tested (the highest level was 11.5 ppb), in the wall insulation of at least 1 mobile home, and in the furnace air filter of at least 1 mobile home. Six soil samples in which dioxin had been detected were also tested for the presence of 132 substances considered either hazardous or priority pollutants by EPA; none

Figure 3-1.—Schematic of the fate of dioxin from the Northeastern Pharmaceutical and Chemical Company plant (8).



of the substances were detected in any of the soil samples (9). Affected areas included 28 mobile homes, a house, the roof of an underground home, soil under an equipment shed, 1,400 feet of highway shoulder, and approximately 5 acres of the park property (10).

On May 12, 1983, the Centers for Disease Control (CDC) (now the Centers for Disease Control and Prevention [CDC]) issued a health advisory which stated that the 29 families living in the park were at risk of developing adverse health effects if they remained in residence. EPA initiated an immediate removal action at the Quail Run Mobile Home Park, including the temporary relocation of the residents.

A security fence was erected by EPA during the week of May 23, 1983. Additional soil samples were collected in July to more precisely define the extent of contamination. Twenty-eight mobile homes were removed from the site and decontaminated. After restoration of the site was completed in April 1987, the park was reoccupied and renamed Fox Creek Estates (11).

Figure 3-2.—Location of the Missouri dioxin sites included in the Dioxin Subregistry of the National

Exposure Registry.



Table 3-1.—Characteristics of the Missouri dioxin sites.

Site Name	Land Use	Maximum Dioxin Level (ppb)*	Year Contamination Level Identified	Potential Population at Risk of Exposure
Shenandoah Stables	Recreational	33,000	1974	100
Minker/Stout/Romaine Creek	Residential	740	1983	100
Times Beach	Residential	980	1982	2,100
Quail Run Mobile Home Park	Residential	2,200	1983	150

*ppb = parts per billion; peak dioxin levels are reported in soil.

Minker/Stout/Romaine Creek

The Minker/Stout/Romaine Creek site, located in Jefferson County, consists of five separate areas, the Minker residence, the Stout residence, Romaine Creek, the Cashel residence, and the Sullins residence. These sites were contaminated when contaminated fill material, originating at the Bubbling Springs Arena, was deposited there in the early 1970s. Because of extensive erosion and runoff, the area of contamination expanded to the point where it was impractical (or impossible) to allow residents to pursue normal activities without significant risk of exposure. As a result of these facts, and the time and complexity involved in developing and implementing a remedial action plan for these sites, EPA offered to relocate the residents (4).

Bubbling Springs Arena

Bubbling Springs Arena is a recreational area on Romaine Creek Road that was used by members for horseback riding and swimming. A 0.6-acre outdoor horse arena was located on the property. The arena was named after Bubbling Springs, which surfaces upstream from the arena and forms a branch that runs parallel to the arena. This branch is a tributary of Romaine Creek.

The arena was sprayed twice in June 1971 with waste oil that contained dioxin. Approximately 2,500 gallons of oil were sprayed on the arena, and then the arena was disked to a depth of approximately 8 inches to mix the oil with the soil (12). Shortly thereafter, six horses became ill and died. At the time, the cause of death was undetermined. As a precaution, however, the owners had the arena floor excavated. The excavated soil was used as fill in nearby residential areas (7).

Samples from the arena were collected by EPA in May 1982 and February 1983. The highest level of dioxin (97 ppb) was detected in a composite sample from the perimeter of the horse arena. The dioxin had migrated and, in addition to being found in the horse arena, was also detected in soils on lands located between the horse arena and Bubbling Springs Creek, and in the pasture area.

Minker Residence

In March 1973, before the soil was analyzed for contaminants, a private contractor used approximately 20 truckloads of soil excavated from the Bubbling Springs arena to fill a steep ravine on the south end of the Minker house. EPA sampled the site in 1982.

The site contamination resulted when the fill was placed in a natural drainageway on a steep slope in a headwaters area of Romaine Creek. Natural erosion, wind transport, and vehicular and pedestrian movement resulted in documented contamination from 0 to 360 ppb as far away as 6,000 yards downgradient in Romaine Creek and at other residences near the site. On the site itself, sampling results ranged from 85 to 740 ppb (8).

Because CDC had determined that long-term exposure to dioxin at >1 ppb presented the possibility of excessive health risks to residents in the contaminated area, eight families were offered the opportunity for permanent relocation.

Stout Residence

The Stout portion of the Minker/Stout/Romaine Creek site became contaminated when dioxin-contaminated soil was used as fill material to create a level surface for two mobile home pads. It is believed that approximately 850 cubic yards of dioxin-contaminated fill material were used as part of a much larger amount of fill required to create this level surface. The site is on the side of a ridge with a natural slope of 30 degrees. The presence of dioxin was confirmed in the gully behind the property (7).

Sample results showed dioxin at this site at levels from 1 to 272 ppb. The CDC health advisory for Minker also covered this site. Three families were offered permanent relocation and moved from the site.

Sullins Residence

In 1972, the Sullins family removed a large tree from a corner of their property, located on Romaine Creek Road, and arranged for a private contractor to deliver about 14 cubic yards of fill dirt to place in the hole. The contractor advised the Sullinses that the soil was from the Bubbling Springs arena and was being removed because it had caused problems with the horses' hoofs; the Sullinses were also told that grass would probably not grow on the site because the soil had been sprayed with contaminated waste oil (7).

EPA sampled the site in December 1982, and results showed dioxin levels ranged up to 99.2 ppb. Additional samples taken in March 1983 showed contamination in the fill area as high as 820 ppb. Access to the fill area was restricted.

Cashel Residence

When Bubbling Springs arena soil was being excavated, Cashel obtained two loads of dirt which he deposited in his backyard, located on Romaine Creek Road. He reported that the dirt was "very smelly". City officials subsequently advised him not to eat vegetables grown in and around the excavated soil. Mr. Cashel reported that no vegetables grew in the soil and that two apple trees died. He scraped up the dirt and piled it at the rear of his backyard. Vegetation subsequently covered most of the contaminated area. The residence is on a ridge line between two forks of Romaine Creek. The grade to the creek is very steep and erosion could have spread the contamination (7).

EPA sampled the site in January 1983, and results showed dioxin levels from 10 to 100 ppb. Additional sampling done in April showed no higher levels of contamination. Access to the fill area was restricted.

Romaine Creek

The Minker residence is located on a ridge at the top of the watershed. One of the biggest problems at the Minker site was the severe erosion that caused considerable contamination in Romaine Creek. Dioxin levels in the creek were reported up to 270 ppb, and dioxin was detected in sediments 2 feet below the surface of the creek bed. Furthermore, bottom-feeding whole fish taken from the Meramec River near the mouth of Romaine Creek showed levels of dioxin >78 parts per trillion (ppt).

Shenandoah Stables

Shenandoah Stables are located on a 6.9-acre tract on Rural Route 1, Moscow Mills, Lincoln County. A 78.5- by 189-foot enclosed arena was sprayed with approximately 2,000 gallons of waste oil containing up to 350 parts per million (ppm) dioxin on May 25, 1971 (8). Shortly thereafter, birds and insects began dying; by August 17, 1971, 12 cats and 4 dogs had died. Of 125 horses exposed to the arena from May 1971 through January 1974, 47 horses died, 25 foals were either stillborn or died shortly after birth, and 23 mares aborted. Some foals were born with deformed legs. A daughter of the stable owner also became sick and was hospitalized for one week. She lost approximately 50% of her body weight before recovering (7).

The stables are in the floodplain of Crooked Creek, a tributary of the Cuivre River. A ditch allows water to flow from the stables to Crooked Creek. The stable area was flooded in December 1982 and in April 1983. Samples collected from the arena floor in August 1971 and analyzed in July 1974 contained from 31,800 to 33,000 ppb dioxin and from 1,350,000 to 1,590,000 ppb polychlorinated biphenyls. In October 1971, 12 inches of soil was excavated from the arena floor and replaced with clean soil. The contaminated soil was put on the southbound lane of Highway 61, which was under construction at the time.

An estimated 2 feet of soil was removed from the arena floor again in April 1972 and deposited in a slough located approximately 75 feet southeast of the stable (12). Trees in the area died the next year. Clean soil and gravel were placed over the fill and some grass, subsequently, grew there. Arena soils were collected for analyses for a second time in August 1974 and no dioxin was detected.

Composite soil samples were collected for a third time from the surface of the arena floor to a depth of 30 inches, and soil samples from around the stable were collected again on May 26, 1982, and analyzed for dioxin. Dioxin levels in these samples ranged from 1.4 to 130.0 ppb. Soils in the slough area where the April 1972 arena floor material was placed contained a maximum concentration of 1,800 ppb dioxin (12). Dust samples taken inside the arena showed contamination from 80 to 100 ppb. Based on this information, the arena was closed.

Times Beach

Times Beach, located in St. Louis County, is an urban, residential setting situated in the floodplain of the Meramec River and has a history of recurring floods. In 1971, all but 5 of the streets of the town, which covered approximately 413 acres, were sprayed for dust control with dioxin-contaminated oil.

An EPA field investigation began in Times Beach in November 1982. Soil samples were collected in late December, and dioxin contamination was confirmed at varying concentrations along the shoulders and in the drainage ditches of streets throughout Times Beach. The population of approximately 2,100 was, therefore, potentially exposed to concentrations of dioxin along roadways ranging from <1 to 980 ppb (4).

Before the laboratory analyses of the samples were completed, a flood struck a major portion of the town and led to the near total evacuation of the community. The flooding raised the possibility of movement of dioxin-contaminated soil from washed-out roadways into the debris and, conceivably, the buildings. Upon receiving the results of the initial laboratory analyses, and while awaiting further environmental sampling to clarify the location, extent, and level of contamination, CDC issued an advisory on December 23, 1982, recommending that the evacuated residents should not return to the town and that clean-up efforts be halted (or performed with full protective gear only on an emergency basis) until additional environmental sampling could delineate the extent of dioxin contamination. This advisory, unlike those at other sites, was issued on an emergency basis to temporarily prevent the repopulation of the town, especially since the main activity of the returning individuals would have been intensive cleanup of the potentially contaminated muddy soil and debris (4).

EPA conducted a second round of soil testing and analysis in January and February 1983. Post-flood environmental sampling results available in February 1983 showed only limited movement of dioxin-contaminated soils; however, based on the extensive amount of contaminated soil in and near the roadbeds, and the continued threat of flooding, and in consideration of the available remedial strategies, EPA decided to offer a phased plan of permanent relocation to the inhabitants of this affected area. On February 22, EPA announced the transfer of $33.1 million from Superfund monies to the Federal Emergency Management Agency (FEMA) to provide a complete buyout of Times Beach businesses and residences. On March 23, the governor of Missouri signed legislation appropriating the required 10% state matching funds. On June 7, FEMA and the state executed an agreement to provide permanent relocation of the affected residents (7).

POPULATION SELECTION

According to Roberts and Bagby (3), about one-third of the dioxin-contaminated sites in Missouri had levels exceeding 100 parts per billion (ppb) dioxin, and half of these were in residential areas. Because they were not uniform in geography, topography, geology, and characteristic land use, the sites varied widely in their potential for human exposure, thus presenting difficulties in public health decision making. Sites with high levels of contamination and those in areas of frequent and regular access constituted the greatest public health risk; however, at other sites, dioxin contamination was in clearly circumscribed areas, at subsurface depths exceeding 15 feet, under paved areas, or in areas with limited land use. All of these factors were considered in assessing the risk of exposure for an estimated 5,000 persons who lived in the contaminated areas from 1971 through 1983.

The Missouri Central Listing (MCL) was developed in order to enable public health agencies to keep in touch with and locate these potentially exposed individuals for educational purposes or possible epidemiologic or clinical followup, or both (4). Baseline and identifying information was collected using the Health Effects Survey (HES) questionnaire constructed to elicit, along with health information, information on exposure risk (that is, residential history; type, frequency, and duration of recreational activities; and occupational history). The questionnaire was administered to individuals or their relatives believed to be at risk of exposure to dioxin. Risk was evaluated based on proximity of residences to a site, possibility of occupational exposure to those working at a site, or frequency of activities on or around a site. However, the criteria for determining what constituted a potential exposure to dioxin were very general and essentially allowed each registrant to define his or her exposure.

For health studies, a subpopulation meeting a more rigorous definition of exposure with explicit criteria to identify dioxin exposure was chosen. This subpopulation comprised people who reported having lived or worked for at least 6 months in areas contaminated with dioxin at levels >100 ppb or for at least 2 years in areas contaminated with dioxin at levels from 20 to 100 ppb, or anyone who participated at least once a week for 6 months in activities that involved close contact with soil contaminated with dioxin at levels >100 ppb or at least once a week for 2 years in activities that involved close contact with soil contaminated with dioxin at levels from 20 to 100 ppb. Activities included gardening, field or court sports, and playing in soil (4).

The 337 persons identified as eligible for the Dioxin Subregistry are a subset of the 2,101 people who are listed on the larger MCL and were selected for the four dioxin-related health studies that were conducted from 1983 through 1986 by the Missouri Department of Health (MDH) in conjunction with the CDC. These studies were the (1) pilot epidemiology study, (2) Quail Run medical epidemiology study, (3) Quail Run follow-up study, and (4) adipose (fat) tissue study. The participants of these past dioxin health or epidemiologic studies served as the specific population from which members of the Dioxin Subregistry were selected. The Agency for Toxic Substances and Disease Registry (ATSDR) used this criterion for subregistry eligibility because people in each of the four studies were residents of housing units where there was documentation strongly suggesting exposure to dioxin. All people who participated in one or more of the four studies were asked to participate in the Dioxin Subregistry. Since the studies form the basis from which Dioxin Subregistry participants were selected, each will be briefly reviewed. The results of the studies are included in Section 6.

Pilot Epidemiology Study

In 1983, CDC selected 130 persons for inclusion in a pilot epidemiology study from 800 individuals or their relatives believed to be at risk of exposure to dioxin because they lived near, worked at, or frequently participated in activities near a contaminated site based on MCL data. A high-risk group was selected from this pool based on considerations of duration of exposure to, types of activities at, and extent and magnitude of contamination at dioxin-contaminated areas. In general, the 82 persons in this group had the longest periods of exposure (up to 12 years) to the highest levels of soil contamination (as high as 33,000 ppb) or reported having the most frequent high-soil-contact activities in these highly contaminated areas. The purpose of this selection was to maximize the likelihood of identifying individuals with potential dioxin-related health effects.

A group of "low-risk" individuals was selected mostly from the 800 respondents with the lowest risk of exposure based on the type of exposure site, age, sex, race, and socioeconomic status characteristics in a 2:1 ratio of HIGH:LOW risk subjects. This group comprised 40 persons who had not reported any access to or regular high-soil-contact activities in any known contaminated areas.

The two groups were compared using their responses on the HES questionnaire and results of a clinical protocol composed of physical, neurologic, dermatologic, hematologic, immunologic, and liver function testing (13).

Quail Run Medical Epidemiology Study

For current and former residents of the Quail Run Mobile Home Park, a comprehensive investigation was conducted that used the HES questionnaire, as well as medical and laboratory tests (9). This population was selected for study because of high levels of dioxin contamination found throughout the environs of the mobile home park, including inside many of the homes. An exposed group of 154 persons and a comparison group of 155 persons participated in the study. These people were evaluated under a protocol similar to that used in the pilot epidemiology study. In addition, more specific tests of neurobehavioral parameters (the World Health Organization's core battery for field studies of people potentially exposed to neurotoxins); quantitative tests of tactile, vibratory, and thermal sensations; and additional laboratory tests (serum IgG and creatine assays, urine cultures, assays of cytotoxic T-lymphocyte production, and liver function tests of microsomal enzyme induction) were used.

Quail Run Follow-up Study

In 1986, a follow-up study was carried out on persons from the Quail Run epidemiologic study who were anergic or relatively anergic (14). All exposed and unexposed participants from the first study who did not respond to any of the delayed-type hypersensitivity skin tests antigens ("anergic") or who responded to only one antigen ("relatively anergic") were contacted and asked to return for repeat testing. Of those contacted, 28 exposed and 15 unexposed persons were enrolled in the follow-up study.

A medical, residential, and occupational history was taken on each participant to update medical and exposure information collected during the first study. Complete blood cell counts with differentials and quantitative serum immunoglobulin tests were performed. In vitro lymphocyte tests, including T-cell surface markers (T3, T4, and T8), lymphocyte proliferative responses to mitogens and tetanus toxoid, and allogenic T-cell cytotoxicity, were conducted. Finally, the Multisite CMI skin test was conducted.

Adipose (Fat) Tissue Study

HES questionnaires were used to identify 400 persons as having had high-risk exposures by the criteria mentioned previously for health studies. A total of 59 persons agreed to participate in the adipose tissue study, in which each participant donated approximately 20 grams of subcutaneous adipose tissue from the anterior abdominal wall. These samples were evaluated for the presence of dioxin and compared with similar samples from a control group.

Summary

In summary, the participants in these studies were not mutually exclusive. People selected for the adipose tissue study included 11 persons who were also part of both Quail Run studies, 5 persons from the pilot epidemiology study, people involved in occupational exposure (stable workers from several horse arenas), and people involved in recreational exposure. The total number of participants in the four studies was 353, representing 337 unique individuals.

Of the 337 persons identified as eligible, contacted, and asked to participate in the Dioxin Subregistry, 246 agreed to participate; 4 deceased eligible persons were identified and also included. The remaining people either chose not to participate (17 persons), were in litigation over the site and chose not to participate (6 persons), were incapacitated and no proxy available (3 persons), were not at home after 8 attempts to contact (11 persons), or ineligible (1 person). ATSDR was unable to locate 49 eligible persons.

ON-SITE ACTIVITIES

In the summer of 1989, data collection for the Dioxin Subregistry began with telephone interviews (face-to-face interviews had been conducted for previous health studies) with potential subregistry members from Missouri. People who had participated in one of the four previously mentioned Missouri health studies were considered to be "potential" registrants.

Preparations for on-site data collection included a mailing of an information packet to potential registrants. The mailing consisted of a question-and-answer brochure that contained information about ATSDR, the National Exposure Registry, the Dioxin Subregistry, and the chemical dioxin. It also included a chapter from the ATSDR Toxicological Profile for Dioxin, which summarized all that was known about the association of adverse health outcomes and exposure to dioxin (6). This information packet was sent to residents before the data collection effort began. Soon after the mailout, interviewers began telephoning potential registrants.

A computer-assisted telephone interview (CATI) system was used to collect data. Each eligible person or a proxy for that person was administered the National Exposure Registry questionnaire that included a set of questions about health conditions that the registrant currently had or had ever had and that had been either confirmed or treated by a health practitioner. Each time the respondent reported the presence of one of these health conditions, a set of follow-up questions was asked about the date of first treatment by a physician, current treatment, prescribed medication, and hospitalization related to the condition. Demographic and occupational information was also collected.

Information on deceased eligible persons was obtained from a knowledgeable proxy (usually the spouse) in order to request a death certificate from the appropriate state office. Information on cause of death, along with other pertinent information, was extracted from the death certificates and coded as copies of death certificates were obtained from the states.

The first followup was conducted in 1990; the second followup was conducted in 1991. In both cases, a letter was mailed to registrants announcing the upcoming activity. Interviews were conducted using the same questionnaire and administered using a CATI system.

For the baseline activities, information was obtained for 250 persons (246 living and 4 deceased); for the first followup, 226 persons (221 living and 5 deceased); and for the second followup, 208 persons (203 living and 5 deceased). The response rate (the percent of those eligible who were contacted and asked to participate) for the baseline was 91%, for the first followup, 96%, and for the second followup, 96%.

SECTION 4

COMPARISON OF DIOXIN SUBREGISTRY DATA

AND NATIONAL DATA

REGISTRANT DESCRIPTIVE DATA

At baseline there were 250 members of the Dioxin Subregistry-246 living and 4 deceased. Of the 246 living registrants, 207 (84.1%) completed the interview themselves; 39 (15.9%) required a proxy because of age or a disability. Death certificates were obtained for the four deceased members; however, because of the small number, the deceased component of the population was not included in the statistical analyses and is not discussed further in this report. Tables 4-1 and 4-2 contain information on the characteristics of the 246 registrants alive at the time of the baseline interview. Information from all sites is included in these tables.

Table 4-1 shows that 47.2% of the registrants were female. The table also shows that 41.9% of the registrants were from 25 through 44 years of age and 13.4% were under the age of 18 years. One registrant refused to answer the age question and, therefore, was excluded from all analyses involving age. The Subregistry data were collected in 1989 and were limited to those who participated in the health studies conducted during or prior to 1985; therefore, any registrants less than 5 years of age were excluded. About 98% of the Dioxin Subregistry population were white, indicating an overall overrepresentation of whites compared with the general U.S. population.

Of the registrants 25 years of age or older, 73.4% had at minimum a high school diploma. More females than males had completed high school (52.9% versus 43.3%) or some college (19.5% versus 15.5%). However, a higher percentage of males (10.3%) than females (5.8%) had completed college or some post-college education. (See Table 4-1.)

Of the registrants 19 years of age or older, 73.4% were employed either full- or part-time at the time of the interview; this percentage varied substantially between males and females: 81.1% for males versus 64.6% for females.

Table 4-2 provides data on the registrants' use of tobacco products. Of the 212 registrants 18 years of age or older, 38.2% reported being current cigarette smokers (smoked more than 100 cigarettes, smoked at time of interview); 43.4% of females and 33.6% of males were current smokers. More females than males (37.4% versus 29.2%) reported having never smoked cigarettes. A small number of the registrants reported ever using other tobacco products: pipes (10.8%), cigars (10.4%), snuff (3.8%), and chewing tobacco (9.5%). The smoking rates of the registrants were compared with national rates, and the results are reported later in this section.

RATIONALE FOR THE COMPARISON OF THE

DIOXIN SUBREGISTRY DATA WITH NATIONAL DATA

This section includes comparisons of Dioxin Subregistry data with data from national surveys. These comparisons are consistent with the Registry objectives and goals as stated in the Policies and Procedures Manual (1); one of the goals is to provide a preliminary assessment of the extent of excess

Table 4-1.—Descriptive data for living registrants (all sites).

Variable	Males		Females		Total
	N	(%)	N	(%)	N	(%)
Sex	130	(52.8)	116	(47.2)	246	(100.0)
Age (years) £17 18-24 25-44 45-64 ³65 Missing	17 16 51 37 9 0	(13.1) (12.3) (39.2) (28.5) (6.9) (0.0)	16 12 52 25 10 1	(13.8) (10.3) (44.8) (21.6) (8.6) (0.9)	33 28 103 62 19 1	(13.4) (11.4) (41.9) (25.2) (7.7) (0.4)
Education (³25 years of age) Not high school graduate High school graduate Some college College graduate or more	30 42 15 10	(30.9) (43.3) (15.5) (10.3)	19 46 17 5	(21.8) (52.9) (19.5) (5.8)	49 88 32 15	(26.6) (47.8) (17.4) (8.2)
Occupational Status (³19 years of age) Currently employed Previously employed Never employed	90 21 0	(81.1) (18.9) (0.0)	62 33 1	(64.6) (34.4) (1.0)	152 54 1	(73.4) (26.1) (0.5)

adverse health conditions, if reported by Dioxin Subregistry members. Another objective is to generate-rather than test-hypotheses about dioxin exposure and health outcomes.

In addition to a comparison of Subregistry health data with national health data norms, this section includes a comparison of registrant demographic and smoking data with national data. These comparisons of demographic characteristics and smoking rates indicate the extent to which Dioxin Subregistry members are similar to the general population. Such comparisons are important because certain demographic characteristics and smoking are known to be correlated with or are probable causes of adverse health conditions. What must be kept in mind when carrying out the statistical analyses and interpreting the results is the small number of registrants. The statistical power (the power to reject no difference when the converse is true) is substantially lowered when the sample size is this small.

Table 4-2.—Tobacco use data for Dioxin Subregistry registrants 18 years of age or older (all sites).

Variable	Males		Females		Total
	N	(%)	N	(%)	N	(%)
Sex	113	(53.3)	99	(46.7)	212	(100.0)
Cigarettes* Current smoker Ex-smoker Never smoked	38 42 33	(33.6) (37.2) (29.2)	43 19 37	(43.4) (19.2) (37.4)	81 61 70	(38.2) (28.8) (33.0)
Pipes Current smoker Ex-smoker Never smoked	2 21 90	(1.8) (18.6) (79.6)	0 0 99	(0.0) (0.0) (100.0)	2 21 189	(0.9) (9.9) (89.2)
Cigars Current smoker Ex-smoker Never smoked	4 18 91	(3.5) (15.9) (80.5)	0 0 99	(0.0) (0.0) (100.0)	4 18 190	(1.9) (8.5) (89.6)
Snuff Current user Ex-user Never used	3 5 105	(2.7) (4.4) (92.9)	0 0 99	(0.0) (0.0) (100.0)	3 5 204	(1.4) (2.4) (96.2)
Chewing Tobacco Current user Ex-user Never used	8 11 94	(7.1) (9.7) (83.2)	0 1 98	(0.0) (1.0) (99.0)	8 12 192	(3.8) (5.7) (90.6)

*Current smoker - 100 or more cigarettes in lifetime; smoked at time of interview.

Ex-smoker - 100 or more cigarettes in lifetime; did not smoke at time of interview.

Never smoked - Smoked less than 100 cigarettes in lifetime.

SELECTION OF THE NATIONAL COMPARISON POPULATION

Dioxin Subregistry baseline data were compared with data obtained from the 1989 National Health Interview Survey (NHIS)(15). The NHIS data were used in the comparison of both demographic and health data. The 1989 NHIS survey did not include questions about cigarette smoking for the subpopulation that was used for the data analyses, the results of which are presented in this report. Hence, smoking could not be included as a factor in the models used for the NHIS statistical comparisons. Smoking rates for the Dioxin Subregistry were compared with national rates derived from several sources other than the NHIS database.

An appropriate subset of the NHIS database was selected for comparison with the National Exposure Registry (NER). The NHIS population is an appropriate comparison population because it is a representative subset of the residential, noninstitutionalized U.S. population, the population of interest for comparisons of the health status of the National Exposure Registry members. As of 1985, a stratified, multistage cluster sample design was used in the NHIS to obtain a representative sample of the target population; this information was used to create representative national norms. The weighting factors provided by the National Center for Health Statistics (NCHS) (15) were applied when using the data; otherwise, because of the NHIS sample design, the estimates would have been biased. The subset of the 1989 NHIS file used for the selected comparisons in this report comprised 116,929 respondents. The NHIS file, like the Registry file, is composed of self-reported data; the data collection instruments used were very similar. Because of the similarity of the data collection instrument used by the NHIS and the National Exposure Registry, the NHIS data were appropriate for the calculation of selected prevalence and period prevalence figures and could be used for exploratory comparison with Registry data for health outcomes. However, the mode of data collection differed: the NHIS data were collected using face-to-face interviews; the Dioxin Subregistry data by telephone interviews.

The Dioxin Subregistry sites and members are located primarily in the midwestern United States (in the Times Beach, Missouri, area), with the remainder located throughout the United States. Despite the regionality of the Dioxin Subregistry when compared with the NHIS, ATSDR's review of the regional rates for selected outcomes found no definitive evidence indicating that the overall health status of midwesterners differed significantly from that of the general U.S. population; in particular, there did not appear to be a regional difference for the outcomes reported in excess by the Dioxin Subregistry population. Rates of occurrence for selected chronic conditions are listed by geographic regions-Northeast, Midwest, South, and West-in an NCHS publication (16). Of the five health conditions reported statistically significantly more often by the Dioxin Subregistry members, none were higher for the Midwest region. It does not appear, therefore, that regional differences accounted for the increased registrant reporting found for some health conditions.

METHODS OF DESCRIPTIVE VARIABLE COMPARISONS

Demographic Characteristics

The NHIS and Dioxin Subregistry samples were compared in terms of four demographic characteristics: sex, age, race, and education level. Each of these variables and cigarette smoking are potential correlates, either directly or indirectly, with health status. Therefore, it was necessary to explore the comparability of the NHIS and Dioxin Subregistry data files for these variables. The procedures used to carry out the file comparisons follow.

Sex

The sex distributions were compared for the total populations on an age-specific subpopulation basis. Each age-specific proportion (of males or females) in the Dioxin Subregistry was compared with the corresponding standard proportion derived from the NHIS using a one-sample test for a binomial proportion (17); the NHIS proportion was used as the null value. When the normal approximation did not hold, two-tailed mid-p values were computed (17-19).

Age

Age was divided into seven categories. As discussed previously in this section, the fact that the exposure ended or occurred before 1985 created a minimum age for registrants. Comparability of sex-specific age distributions between the NHIS and Dioxin Subregistry members was assessed by performing chi-squared goodness-of-fit tests. Expected counts were generated by applying the NHIS proportions for each sex-age category to the appropriate Subregistry totals.

Race

Race is an established correlate of socioeconomic status (20) and health status (21). National data indicate that nonwhites have lower rates for cigarette smoking (22). For these reasons, race is a potential independent variable for the comparisons of health status and smoking rates. As was discussed previously in this section, there were only five nonwhites (2%) in the Dioxin Subregistry; because of this small number and because there are no known health effects associated with the race reported by the nonwhite registrants, all registrants were included in the analyses. The NHIS comparison group was restricted to those reporting race as white.

Education Level

The descriptive analyses included comparisons for education level (the highest level attained as reported by the respondent); a three-category ordinal variable was created. The categories used were 0 through 11 years of education, 12 years of education (or the equivalent of a high school diploma), and 13 or more years of education. For the these analyses, education was used as a surrogate for socioeconomic status; because this is difficult to interpret for school-aged children, analyses incorporating the variable education level were restricted to those 19 years of age or older. The sex-specific education distributions for registrants and NHIS members were compared using chi-squared goodness-of-fit tests.

Cigarette Smoking

Rates for current and past smoking behavior were compared with national data from several independent sources. For the analyses, a current smoker was defined as someone who reported being a smoker at the time of the interview and who had smoked at least 100 cigarettes in his or her lifetime. An ex-smoker was defined as someone who had ever smoked at least 100 cigarettes during his or her lifetime. People who were classified in the "ever smoked" category included both current and ex-smokers.

As discussed earlier, the 1989 NHIS file, the data file used for comparing health rates, did not contain complete smoking information for the subpopulation used in the data analyses. Therefore, the variable "smoking" could not be included as an independent factor in the statistical models. However, although smoking data were not collected for all respondents, information was collected on a sufficiently large segment (although not all) of the 1990 NHIS (23) population to calculate meaningful national rate estimates that could be used to compare with the Subregistry rates. In addition to these rates, the Subregistry rates were also compared with the national rates derived from the Behavioral Risk Factor Surveillance System (BRFSS) (24) and the 1990 National Household Survey on Drug Abuse (NHSDA) (22).

METHODS OF COMPARING HEALTH OUTCOMES

Question Comparability

The reporting rates for the Dioxin Subregistry and NHIS data were compared for each health condition. One of the factors determining the validity of the results of these comparisons was the comparability of NHIS and Dioxin Subregistry health condition questions; therefore, the comparisons were preceded by an assessment of the question comparability. The health condition questions differed in three respects: restrictions on the source of diagnosis; the time frame of occurrence or treatment; and, in some cases, the wording of the health condition. A discussion of the potential variability for the health condition questions follows. The NHIS health-related questions are presented in Appendix A and the Dioxin Subregistry health-related questions in Appendix B.

Source of Diagnosis

Dioxin Subregistry questions about health conditions specified that the source of diagnosis must be a physician or other medical provider. This qualification was intended to minimize self-diagnoses or the biased reporting of health problems by registrants that might have occurred because of an increased awareness of health due to the registrants' knowledge of the exposure and the publicity related to that exposure. The NHIS questions did not include any type of limitation or qualification concerning the source of diagnosis. Therefore, if all other factors were similar or equal, an increased reporting might be expected by NHIS respondents when compared with the Dioxin Subregistry registrants.

Time Frame

The Health Information section of the Baseline questionnaire for the Dioxin Subregistry inquired about diagnosis or treatment of conditions in one time frame-ever had (subject's lifetime). The question was phrased "Has a physician or other medical provider ever told you/SUBJECT that you/he/she had or treated you/SUBJECT for ... [condition]?"). Respondents who reported yes to this question were then asked whether they or the subject was ever treated for the condition, date of first treatment for the condition, and whether they were currently being treated for the condition.

The NHIS questionnaire focused on three different time frames. Depending on the specific condition, respondents were asked if they ever had, had within the past year, or currently had (at the time of interview) the condition. Dioxin Subregistry baseline questions about health conditions asked about diagnoses of or treatment for conditions from the point of birth through the date of the interview ("Has a physician or other medical provider ever told you/SUBJECT that you/he/she/ had or treated you/SUBJECT for CONDITION?"). Only one time frame was addressed: ever had (subject's lifetime). Respondents who reported "yes" to this question were also asked whether the subject was ever treated for the condition, when the subject was first treated for the condition, and whether the subject was currently being treated for the condition.

The NHIS questionnaire included questions that focused on three time frames-ever had the condition, had the condition within the last 12 months, or currently had the condition. With the exception of heart disease, only one time frame was used to create a reponse rate for any given health condition. The NHIS data file heart disease rate reflected a composite of responses to heart-related questions that were asked in both the "ever" and "12-month" time frames. The NHIS questionnaire asked whether respondents had ever had the heart conditions rheumatic, congenital, or coronary heart disease; angina pectoris; myocardial infarction; or any other heart attack; in the last 12 months time frame for damaged heart valve, tachycardia or rapid heart, heart murmur, or other heart trouble. In addition, for some heart-related questions, a positive response was discarded if the respondent did not answer positively to one or more other selected questionnaire items (16). A comparable heart response rate could not be created for the NER file and, therefore, a comparison with national norms could not be made for the heart condition variable.

For the other health conditions, the time frames were standardized to make the NHIS and Dioxin Subregistry rates directly comparable. Table 4-3 provides a comparison of NHIS and Dioxin Subregistry questions in terms of the time frame for each health condition. One NHIS health condition question, the effects of a stroke, was asked and rate calculated in the context "have you ever had". The questions and time frames for the subregistry and NHIS matched on this condition.

Eleven of the NHIS questions were asked in the time frame "in the past 12 months."For hypertension, the NHIS 12-month response rate was calculated using the "ever had" positive responses; however, the positive response was retained in the file only if the respondent also answered positively to one or more of nine other selected questionnaire items (16). This additional restriction might have reduced the NHIS response rate for this condition. For these 12 health conditions (see Table 4-3), the Dioxin Subregistry time frames for comparison were adjusted. In the Dioxin Subregistry, a health condition was defined as occurring "in the past 12 months" if (1) the reported date of first treatment was within the 12 months preceding the interview or (2) the subject was receiving treatment at the time of the baseline interview. This adjustment could have resulted, however, in an underestimation of these 12 conditions for Dioxin Subregistry data for the following reason. A year or more before the baseline interview, a registrant might have been told that he or she had (or was treated for) one of these 12 health conditions, but was not being treated at the time of the interview. If so, such a registrant would not have been included in the rates for these 12 health conditions.

Table 4-3.—Comparison of time frames for health condition questions.

Dioxin Subregistry Conversion from "ever had" to	NHIS Version: "ever had"	NHIS Version: "in the past 12 months"	NHIS Version: "now have"
"Ever had"	Stroke
"in the past 12 months" ("ever had" and "currently have" and/or date of 1st treatment within past 12 months)		Cancers (all), rash, anemia, kidney disease, urinary tract disorders, ulcer, liver problems, asthma, respiratory problems and allergies, diabetes, arthritis, hypertension
"now have" ("ever had" and "currently have")			Speech impairment, hearing impairment, mental retardation

There were three health conditions in the NHIS questionnaire that were queried in the time frame "do you now have". These conditions were speech impairment, hearing impairment, and mental retardation. The time frame for the comparable Dioxin Subregistry health conditions was adjusted by counting only registrants who reported that they were "currently receiving treatment" for one of these three conditions. Again, if all other factors were equal or the same, an increased reporting by the NHIS respondents when compared with the Dioxin registrants would have been expected.

Health Condition Specification

Dioxin Subregistry and NHIS questions were also compared in terms of the phrasing of the health conditions. As Table 4-4 indicates, some health conditions matched exactly, while others did not match as closely. An ATSDR panel of scientists and physicians determined reasonable matches for the Dioxin Subregistry health conditions and specific NHIS conditions (ICD-9 codes (25), or NHIS condition recodes (15)).

The nine health conditions in Class A of Table 4-4 either matched exactly or the Dioxin Subregistry version was inclusive of the NHIS version. That is, the NHIS wording of the health condition and the NHIS classification of the condition in the recodes were the same as or paralleled very closely the corresponding Dioxin Subregistry item. Class B included eight health conditions that did not match as closely, but were considered to be sufficiently similar for the purposes of the NHIS and Dioxin Subregistry comparisons. In only one case (urinary tract disorders) was there a potential for excess reporting by registrants when compared with the NHIS population because of the wording of the questions. For all other questions, related factors being consistent for the two populations, the question phrasing would have potentially resulted in higher reporting rates by the NHIS population.

Table 4-4.—Comparison of Dioxin Subregistry and National Health Interview Survey health questions.

Q#*	Wording in Dioxin Survey	National Health Interview Survey Definition	NHIS Chronic Recodes†	ICD-9§
Class A¶
6	Hypertension	Same	C508	401-5
8	Kidney disease	Kidney stones Kidney infections Other kidney trouble	C409-11	592 590 581-3 593
10	Effects of stroke	Cerebrovascular disease	C509	430-8
14	Liver problems	Liver disease, including cirrhosis	C302	571-2 573.0,.3-.9
15	Asthma, emphysema, or chronic bronchitis	Same	C601-2 C609	490-1 492 493
16	Other respiratory allergies or problems such as hay fever	Hay fever Allergic rhinitis without asthma	C603	477
17	Diabetes	Same	C403	250
22	Hearing impairment	Deaf - both ears Other hearing impairment	C203-4	X05 X06-9
25	Mental retardation	Same	C208	X19
Class B**
3	Cancer	Some cancers queried directly; others ascertained indirectly		140-208
5	Skin rashes, eczema, or other skin allergies	Psoriasis Dermatitis Dry (itching) skin	C112-4	696 690-4 698.9
7	Anemia or other blood disorders	Anemia of any kind	C404	280-5
9	Urinary tract disorders, including prostate trouble	Disorders of the bladder (other than bladder infections) Diseases of prostate	C413-4	594.1 596 600-2 (except 601.4)

Table 4-4.—Continued.

Q#*	Wording in Dioxin Survey	National Health Interview Survey Definition	NHIS Chronic Recodes†	ICD-9§
Class B**
13	Ulcers, gall bladder trouble, or stom- ach or intestinal problems	Gallbladder stones Gastric, duodenal, or peptic ulcer Abdominal hernia Gastritis and duodenitis Disease of esophagus Other functional disorders of stomach or digestive system (not indigestion) Enteritis and colitis Spastic colon Diverticula of intestines Other stomach and intestinal disorders (not constipation)	C301 C303-8 C310-3 C315	574 530-7 550-3 555 556 558 560-2 564.1 569 787
18	Arthritis, rheumatism, or other joint disorders	Arthritis Rheumatism Gout Sciatica (and lumbago) Intervertebral disc disorders Bone spur and tendinitis Disorders of bone or cartilage Bursitis	C101-7 C109	711.0, .9 712.8-.9 714-6 720.0 721 729.0 724,.2-.3 722, 726 727.0, .2-.9 730.0-.3, .9 731.0, .2 732-3
19	Rheumatic fever, heart disease, or other heart problems	Rheumatic fever Ischemic heart disease Heart rhythm disorders Congenital heart disease Other select heart diseases	C501-7	390 392-9 410-4 427.0-.6,.8-.9 785.0-.2 745-6 415-7 420.9 421.0, .9 422.9 423-4 425.0-.5, .9 426, 428 429.0-.6,.8-.9
20	Speech impairment	Stammering and stuttering Other speech impairment	C205-6	X10 X11

*Question in Dioxin Subregistry questionnaire.

†Chronic Recodes, National Health Interview Survey Public Use Data Tape Documentation (15).

§ICD-9 is the International Classification of Diseases, 9th Revision, World Health Organization (WHO) (25).

¶Class A indicates questions match exactly or closely.

**Class B indicates questions are similar.

For six of the health conditions on the Dioxin Subregistry questionnaire, there were no parallel items in the NHIS questionnaire. These conditions pertained to symptoms-frequent periods of fatigue or tiredness; frequent periods of nausea; seizures, tremors, spells, or epilepsy; weakness, paralysis, or numbness in the arms or legs; frequent periods of anxiety, nervousness, or depression; and frequent or severe headaches. Unlike some of the national health surveys (26), environmental studies commonly ask about symptoms as well as health outcomes. Data on these symptoms, while not directly comparable with NHIS data (and not discussed in this report), are important in assessing impact of environmental contaminants on health and will be useful for making comparisons with past and current epidemiologic environmental studies, as well as future longitudinal studies.

The Dioxin Subregistry questionnaire was used to obtain information, via an open-ended questionnaire, on all types of cancers. The NHIS questionnaire, however, directly queried the respondents on only specific types of cancer-including skin, stomach, intestinal, colon, rectal, lung, breast, and prostate cancer. Information on other cancers was obtained indirectly by querying the respondent on hospital stays, doctor visits, and restricted activity. The NHIS question is worded, "In the last 12 months, did anyone in the family have (specific site) cancer?" The NHIS time frame restriction and the possible restriction on types of cancers reported for the NHIS file makes the results of the comparison with the Dioxin Subregistry data uncertain and the interpretation tenuous.

Statistical Analysis of Health Data

Standardized morbidity ratios were computed for each health condition. The risk ratios were calculated as the sum of the stratum-specific observed events divided by the sum of the stratum-specific expected events derived from a standard population (27). The expected number of events for a particular sex-age stratum was computed by applying the sex-age-specific prevalence or period prevalence rate from the NHIS to the corresponding sex-age-specific denominator of the Dioxin Subregistry. The 99% confidence intervals (CIs) for the ratios were generated using exact methods, with the observed counts assumed to follow the Poisson distribution (27). The sparseness of the data precluded a detailed statistical analysis of the sex-, age-, and sex-age- specific observed/expected (O/E) ratios. The O/E ratios are presented in Appendices C-1 through C-16. For conditions in which the observed and expected counts were considered to be sufficiently large, exact 99% CIs similar to those mentioned previously were computed for the sex-specific O/E ratios. No adjustments were made for multiple comparisons.

The complex sampling design of the NHIS was accounted for when computing rates (15). Numerators for a given sex-age stratum were computed by summing the cross product of the "condition weight" and the "basic final weight" for people who were asked the appropriate "condition list" and responded positively for the condition of interest. Since the presence of cancer could be ascertained from several sources within the NHIS questionnaire, stratum-specific numerators were computed by summing the "basic final weight" for all people with cancer. Denominators were obtained from the NHIS "person" records by summing the "basic final weight" for all people in a particular stratum.

RESULTS OF DESCRIPTIVE COMPARISONS

This section provides a discussion of the results of the analyses completed to assess the comparability of the descriptive data-the demographic information and smoking history- between the Dioxin Subregistry and NHIS files.

Demographics

Race

In the Dioxin Subregistry sample, 98% (n = 241) of the registrants selected their race as white. As discussed earlier in this section, because of the small number of nonwhites in the Subregistry population compared with the NHIS population, only whites are included in the NHIS comparison population used in this report.

Sex

Table 4-5 provides comparisons of the proportion of males within age categories for the Dioxin Subregistry and the NHIS populations. The proportion of females can be calculated as unity minus the proportion of males; the p values are identical when comparing the proportions for females. No statistically significant differences were found in any of the age categories examined. The 55 through 64 years of age category exhibited borderline significance; there were more males in the Subregistry than expected.

Age

The age distributions of the Dioxin Subregistry and the NHIS populations are presented in Table 4-6. These distributions were compared statistically, stratified by sex, using chi-squared goodness-of-fit tests. For males, the age distribution of the Subregistry population was not statistically significantly different from that of the NHIS population (p = 0.11). A marginally significant difference was detected for the female subpopulation (p = 0.08), with the primary disparity occurring in the 65 years of age and older category; fewer registrants fell in this category than were expected.

Education

The distributions of the variable highest level of education attained for the Dioxin Subregistry and the NHIS participants 19 years of age or older are presented in Table 4-7. These distributions were statistically compared using chi-squared goodness-of-fit tests on a sex-specific basis.

The distribution of education level for males in the Subregistry was statistically significantly different from that of the males in the NHIS (p = 0.002). The Subregistry population contained a higher percentage of male members with less than 12 years of education (28.8% versus 20.3%) than expected based on NHIS figures and a lower percentage of college educated males (27.0% versus 43.5%). For females, the Subregistry education distribution was marginally statistically significantly different from that of the NHIS (p = 0.07). There was a higher percentage of females with only a

Table 4-5.—Percentage of males within age groups.

Age (years)	Dioxin Subregistry*	National Health Interview Survey*	p value†
8-17	0.52	0.51	0.96
18-24	0.57	0.49	0.39
25-34	0.45	0.50	0.50
35-44	0.54	0.50	0.55
45-54	0.55	0.49	0.45
55-64	0.68	0.48	0.05
³65	0.47	0.42	0.62

*Cell values are proportions of males for the given age group.

†Two-tailed p value, one-sample test for a binomial proportion

(two-tailed mid-p values were computed when the normal

approximation did not hold).

high school education than expected based on the NHIS rates (54.1% versus 41.3%), and a lower percentage of college educated females (28.2% versus 38.1%).

Cigarette Smoking

Table 4-8 provides smoking rates for registrants 18 years of age or older. The rates for registrants were higher when compared with the national rates for both current smoker and ever smoked categories; the rates were particularly high for women. Also included in Table 4-8 are the rates calculated using the information from the 1990 NHSDA (22). The rates listed are for the total population; in most cases, for the subpopulation reporting race as white, the rates are

about 2 % higher. As when previously compared with national norms, the smoking rates for almost all age and age-sex groups are elevated for the Subregistry population; the female rates from the Subregistry are particularly elevated. The NHSDA population rate for the North Central Region (which includes Missouri) is higher than the national NHSDA levels (32.1% and 30.3 %, respectively) but are still below the Dioxin Subregistry rate (38.2%).

Information gathered under the BRFSS (24) indicated the 1989 U.S. median rate for currently smoking was 24.2% for those 18 years of age or older, and the Missouri rate was 25.9% (compared with the Subregistry rate of 38.2%). When the BRFSS respondents were restricted to those with low education (the education level for whom smoking rates are historically the highest), the rates rose to 29.4% and 30.1% for the United States and Missouri, respectively; these rates compare with the Dioxin Subregistry rate of 38.2% for all education levels.

Table 4-6.—Comparison of the National Health Interview Survey and Dioxin Subregistry age distributions.

Age Group (years)	National Health Interview Survey*	Dioxin Subregistry†
	% of Total	% of Total	Number
Males and Females
8-17 18-24 25-34 35-44 45-54 55-64 ³65 Total	15.0 11.4 19.7 17.0 11.8 10.5 14.7 100.0	13.5 11.4 19.2 22.9 16.3 9.0 7.8 100.0	33 28 47 56 40 22 19 245
Males Only
8-17 18-24 25-34 35-44 45-54 55-64 ³65 Total	15.8 11.5 20.2 17.5 12.0 10.3 12.7 100.0	13.1 12.3 16.2 23.1 16.9 11.5 6.9 100.0	17 16 21 30 22 15 9 130
Females Only
8-17 18-24 25-34 35-44 45-54 55-64 ³65 Total	14.2 11.2 19.2 16.6 11.6 10.6 16.6 100.0	13.9 10.4 22.6 22.6 15.7 6.1 8.7 100.0	16 12 26 26 18 7 10 115

*Cell values are percents based on weighted frequencies.

†One registrant had missing age status.

Table 4-7.—Comparison of the National Health Interview Survey and Dioxin Subregistry education distributions for those 19 years of age and older.

Education Level (years)	National Health Interview Survey*	Dioxin Subregistry
	% of Total	% of Total	Number
Males and Females
£11 12 ³13 Total	20.4 38.9 40.7 100.0	24.6 47.8 27.5 100.0	51 99 57 207
Males Only
£11 12 ³13 Total	20.3 36.2 43.5 100.0	28.8 44.1 27.0 100.0	32 49 30 111
Females Only
£11 12 ³13 Total	20.6 41.3 38.1 100.0	19.8 52.1 28.1 100.0	19 50 27 96

*Cell values are percents based on weighted frequencies.

Table 4-8.—Reported rates of cigarette smoking in the Dioxin Subregistry and comparison population.

Age Group	N	Current Rate*			Ever Rate*
		Subregistry	NHSDA†	NHSDA† (North Central)	Subregistry	NHSDA†	NHSDA† (North Central)
³18 years All Males Females	212 113 99	38.2 33.6 43.4	30.3	32.1	67.0 70.8 62.6	48.6 55.2 42.7	56.5
18-24 years All Males Females	28 16 12	39.3 31.3 50.0	29.6 33.7 25.7	34.2	42.9 37.5 50.0	36.8 40.0 33.8	41.0
25-34 years All Males Females	47 21 26	42.6 42.9 42.3	37.1 39.2 35.0	37.6	68.1 76.2 61.5	53.5 56.3 50.8	53.3
³35 years All Males Females	137 76 61	36.5 31.6 42.6	24.3 27.1 21.8	24.4	71.5 76.3 65.6	55.6 69.3 43.6	58.1

*Rates are number per 100.

†Source: 1990 National Household Survey on Drug Abuse, Substance Abuse and Mental

Health Services Administration (22).

Also, the Dioxin Subregistry current smoking rates exceeded those of the 1990 NHIS (males, 27.9% and females, 23.4%) (23). Unlike the reporting patterns for the 1990 NHIS file and other populations representing national norms, there was an excess in reporting by females over males for most age groups among Dioxin Subregistry members. The overall NHIS rate for males of 32.7% versus 25.8% for females (32.8% versus 28.6% for the East North Central states) compares with the Dioxin Subregistry current smoking rate of 33.6% for males and 43.4% for females.

Table 4-9 presents the ever smoked rates by education level for the Dioxin Subregistry members. As expected from the literature, the general pattern was a decrease in smoking with increased education; the rates for people with no high school diploma were considerably higher when compared with the rates of people with at least a college degree. This overall trend is replicated in other reports as well (28).

Table 4-9.—Smoking rates for the Dioxin Subregistry by educational attainment.

Age Group	Education Level Attained
	No High School Diploma		High School Graduate		Some College		College Graduate*
	Percent†	N§	Percent	N	Percent	N	Percent	N
³18 years All Males Females	75.9 76.5 75.0	54 34 20	69.3 69.4 69.2	101 49 52	57.5 73.7 42.9	40 19 21	47.1 54.6 33.3	17 11 6
18-24 years All Males Females	80.0 75.0 100.0	5 4 1	46.2 28.6 66.7	13 7 6	12.5 25.0 0.0	8 4 4	50.0 0.0 100.0	2 1 1
25-34 years All Males Females	70.0 100.0 40.0	10 5 5	60.9 55.6 64.3	23 9 14	81.8 80.0 83.3	11 5 6	66.7 100.0 0.0	3 2 1
³35 years All Males Females	76.9 72.0 85.7	39 25 14	76.9 81.8 71.9	65 33 32	61.9 90.0 36.4	21 10 11	41.7 50.0 25.0	12 8 4

*May be additional years post-bachelor degree.

†Percent who ever smoked.

§Total number of registrants in this category.

In summary, based on a comparison of smoking rates from the Dioxin Subregistry and national sources, it is possible, because of the increased rates of smoking by Dioxin Subregistry members, that smoking is a factor to be considered, particularly for females, when comparing certain reported health outcomes from the Dioxin Subregistry and 1989 NHIS files. Smoking status must be considered when interpreting findings for outcomes for which it might play a role (29).

RESULTS OF HEALTH OUTCOME COMPARISONS

Standardized morbidity ratios, the ratios of observed events in the Dioxin Subregistry to expected events based on the NHIS and standardized for age and sex, are displayed in Table 4-10 for each health outcome. A value greater than one indicates an excess of positive responses by the Dioxin Subregistry members relative to the number expected based on NHIS rates. The risk ratios

Table 4-10.—Summary of risk ratios for total population.

Condition	Observed (Dioxin)	Expected (National Health Interview Survey)	Risk Ratio	99% CI*
Significantly elevated risk ratios†
Cancers (all)	8	2.25	3.56	1.14, 8.27
Anemia and other blood disorders	12	3.39	3.54	1.46, 7.12
Skin rashes	29	16.00	1.81	1.06, 2.87
Stroke	8	2.11	3.79	1.22, 8.80
Urinary tract disorders	12	3.42	3.51	1.45, 7.07
Significantly lowered risk ratio†
Hearing impairment	3	21.97	0.14	0.02, 0.50
Respiratory allergies	12	25.25	0.48	0.20, 0.96
Nonsignificant risk ratios†
Arthritis	33	39.99	0.83	0.50, 1.27
Asthma, emphysema	15	23.16	0.65	0.30, 1.22
Diabetes	9	6.11	1.47	0.51, 3.28
Kidney disease	8	3.89	2.06	0.66, 4.78
Liver problems	2	0.85	2.36	0.12,10.94
Mental retardation	2	1.18	1.69	0.09, 7.84
Speech impairment	1	1.64	0.61	0.00, 4.55
Hypertension	29	26.58	1.09	0.64, 1.73
Stomach problems, ulcers	25	19.66	1.27	0.71, 2.09

*Confidence intervals.

†Statistically significantly different from 1 at the p = 0.01 level.

for several health conditions were statistically significantly elevated (greater than 1) at the p £ 0.01 level. These were anemia and other blood disorders, all cancers, skin rashes, stroke, and urinary tract disorders. Statistically significant deficits in reporting by the Dioxin Subregistry population were observed for hearing impairment and respiratory allergies.

In addition to the overall risk ratio, the sex-, age-, and sex-age-specific (O/E) ratios are presented in Appendices C-1 through C-16. Sparse data precluded a statistical evaluation of all age- and sex-age group ratios. When the O/E counts were considered to be sufficiently large, exact 99% confidence intervals were generated for the sex- and sex-age group ratios. These results are summarized in Table 4-11. Also, the small O/E counts in many of the sex, age, and sex-age strata make observational interpretation of the data somewhat tenuous. That is, the O/E ratio, the risk ratio, might be quite large, yet its components so small that any change in the numerator (the observed count in the Subregistry) would substantially alter the ratio. A detailed examination of the results for each health outcome follows.

Anemia or Other Blood Disorders

The overall risk ratio of 3.54 (12 observed versus 3.4 expected, 99% CI = 1.46, 7.12) indicated a statistically significant increase in reporting for the Dioxin Subregistry population over that expected based on the NHIS reporting rate. The sex-, age-, and sex-age-specific estimated risk ratios for anemia are detailed in Appendix C-1. The largest excess in reporting by sex was seen for males. The O/E ratio of 7.08 for males (4 observed versus 0.6 expected) was statistically significantly greater than 1.0 (99% CI = 1.19, 22.29). The ages of the four male registrants reporting anemia covered a wide range-age groups 8 through 17 years of age to 65 years of age or older. The risk ratio of 2.83 for females (8 observed, 2.8 expected) was not statistically greater than 1.0 (99% CI = 0.91, 6.57).

Arthritis, Rheumatism, or Other Joint Disorders

The overall risk ratio for arthritis, rheumatism, or other joint disorders was less than one (O/E = 0.83, 99% CI = 0.50, 1.27), indicating fewer positive reports by the Subregistry population than expected, 33 observed versus 40.0 expected. The sex, age, and sex-age group estimates for arthritis are shown in Appendix C-2. Most of the sex-age group ratios were less than one, indicating that the reporting of arthritis was generally lower in the Dioxin Subregistry data than expected based on the NHIS prevalence rates. The one notable exception was the three positive reports for females less than 24 years of age (2 for those 18 years of age or younger), which was higher than anticipated based on NHIS rates (3 observed versus 0.64 expected).

Asthma, Emphysema, or Chronic Bronchitis

The estimated overall risk ratio of 0.65 (99% CI = 0.30, 1.22) was decreased, however, not statistically significantly decreased. The stratum-specific risk ratio estimates are given in Appendix C-3.

Cancers (All)

Comparing the Dioxin Subregistry and NHIS 12-month time frame reporting rates, the overall ratio for all cancers was statistically significantly elevated at the p = 0.01 level (risk ratio = 3.55,

Table 4-11.—Statistically significant* risk ratios for total population and age, sex subgroups.

Condition	Sex	Age	Observed	Expected	Risk Ratio	99% CI† (exact)
Hearing impairment	All Male Female	All All All	3 3 0	21.97 14.87 7.09	0.14 0.21 0.00	0.02, 0.50 0.02, 0.74 0.00, 0.65
							Rash	All	All	29	16.00	1.81	1.06, 2.87
Stroke	All All Male	All 45-54 45-54	8 3 2	2.11 0.17 0.08	3.79 17.79 24.00	1.22, 8.80 2.00, 65.09 1.24, 111.28
Urinary tract problems	All Female Female	All All 65+	12 8 3	3.42 1.44 0.26	3.51 5.56 11.58	1.45, 7.07 1.79, 12.91 1.30, 42.39
Cancers (all)	All	All	8	2.25	3.56	1.14, 8.27
Anemia	All Male All	All All 55-64	12 4 3	3.39 0.56 0.25	3.54 7.08 11.94	1.46, 7.12 1.19, 22.28 1.34, 43.70
Respiratory allergies	All	All	12	25.25	0.48	0.20, 0.96

*Statistically significant at the p = 0.01 level.

†Confidence intervals.

99% CI = 1.14, 8.25). There were 8 reported cancer cases-3 thyroid, 1 bladder, and 4 skin cancers (See Table 4-12); 2.5 cases were expected based on NHIS reporting rates. Appendix C-4 shows the results for the cancers reported using the NHIS 12-month period prevalence rates as comparison values. There were a number of O/E subgroup ratios greater than 1.0; however, none were statistically significantly greater than 1.0. For example, the estimated risk ratio for females was 4.25, 5 cases observed versus 1.18 expected. All five cases occurred in women 45 years of age or older, with three occurring in those 65 years of age or older. A further analysis of the thyroid cancers, which were in excess of the number expected based on the Surveillance, Epidemiology, and End Results (SEER) program (30) (the SEER rate for white females is about 7.0 per 100,000), showed that the date of first treatment occurred before 1972 for one case and in the mid-1970s for a second case; two were females and one was male. This information indicated that, in all probability, the excess thyroid cancers were not related to exposure to dioxin.

When the time frame for reporting was ever had, the registrants reported 17 cancers (see Table 4-13) versus 8 for the last 12-month time frame. Five of the additional nine cases were females who reported positively (three in the 25 to 34 years age group) to having been told they had or

Table 4-12.—Types of cancer in the Dioxin Subregistry reported by age group and sex (time frame is last 12 months).

Age (years)	Type of Cancer*
	Male	Female
8-17
18-24
25-34	Thyroid (1)
35-44
45-54	Bladder (1)	Thyroid (1)
55-64	Skin (1)	Skin (1)
³65		Skin (2) Thyroid (1)

*Numbers in parentheses represent

number of cases.

treated them for cervix uteri or body of uterus cancers. Also of note is that of the 17 cancers reported, only 1 reported the date of first treatment as before 1972, 3 as mid- or late-1970s, and the remainder the 1980s.

Diabetes

None of the risk ratios, overall or sex-specific, were statistically significantly elevated for diabetes. Age and sex group details appear in Appendix C-5. Increased reporting was found for groups older than 35 years of age, with most excesses in the female groups. The largest excess (O/E = 4.36, 3 reported versus 0.70 expected) occurred in females aged 45 through 54 years.

Hearing Impairment

The overall risk ratio of 0.14 (99% CI = 0.02, 0.50) reflects 3 cases observed versus 22.0 expected. This reversal (increased reporting by NHIS versus registrants), seen for both males and females, was predictable. The restriction that Subregistry cases must have been confirmed or treated by a health care provider and NHIS cases did not could have resulted in substantially less reporting by the Dioxin Subregistry participants relative to NHIS reporting rates. The stratum-specific risk ratio estimates for hearing impairment are presented in Appendix C-6. Decreased reporting was observed in the Dioxin Subregistry data for most subgroups.

Table 4-13.—Types of cancer in the Dioxin Subregistry, reported by age group and sex (time frame is ever had).

Age (years)	Type of Cancer*
	Male	Female
8-17
18-24
25-34	Thyroid (1)	Cervix uteri (3) Head, face, neck (1) Uterus (1)
35-44	Leukemia (1)
45-54	Bladder (1)	Thyroid (1) Colon (1) Uterus (1)
55-64	Tongue (1)	Skin (1)
³65	Skin (1)	Skin (2) Thyroid (1)

*Numbers in parentheses represent number

of cases.

High Blood Pressure (Hypertension)

The estimated risk ratios were not statistically elevated for hypertension (O/E = 1.09, 29 observed versus 26.58 expected, 99% CI = 0.64, 1.73). (See Appendix C-7.)

Kidney Disease

The overall risk ratio (risk ratio = 2.06, 8 observed versus 3.9 expected, 99% CI = 0.66, 4.78) was not statistically significantly different from unity. The sex-, age-, and sex-age-specific risk ratio estimates for kidney disease are presented in Appendix C-8. The data are quite sparse; however, the 3 positive reports (versus 0.4 expected) for females aged 25 through 34 years and 4 positive reports (versus 0.5 expected) for males aged 55 years and older are noteworthy.

Liver Problems

The overall risk ratio was 2.36 based on two cases (one each in males and females aged 35 through 44 years). The stratum-specific ratios for liver problems are given in Appendix C-9. The data are very sparse (2 observed, 0.8 expected).

Mental Retardation

Two positive responses were reported for mental retardation, with both occurring in males in the 8 through 17 years of age group (see Appendix C-10 for details). The sparseness of the data precludes meaningful statistical analyses and interpretation.

Skin Rashes, Eczema, or Other Skin Allergies

There was a statistically significant increase in reporting for this outcome by the Dioxin Subregistry population (risk ratio = 1.81, 29 observed versus 16.0 expected, 99% CI = 1.06, 2.87). The greatest excesses occurred for those aged 8 through 17 years and 35 through 54 years (see Appendix C-11 for details). Most of the sex-age-specific ratios were greater than one with few exceptions-namely, males 55 years of age or older and women 65 years of age or older. It should be noted that this is one of the health outcomes for which it would have been predicted that positive reporting would have been reduced in the Subregistry population by the restriction of health care provider confirmation.

Other Respiratory Allergies or Problems, Such as Hay Fever

The overall estimated risk ratio for respiratory allergies was statistically significantly less than 1.0 (risk ratio = 0.48, 12 observed versus 25.2 expected, 99% CI = 0.20, 0.96). Again, this reduced reporting by registrants might reflect the restriction on Subregistry respondents that the condition be confirmed by a health care provider. With the exception of the 8 through 17 years of age group, all of the age-specific risk ratio estimates were less than unity (details are shown in Appendix C-12). There were no observed cases in the age groups 55 years or older; 3.0 were expected based on NHIS rates.

Speech Impairment

For speech impairment there was only one positive response in the Dioxin Subregistry, thus precluding meaningful statistical analyses (see Appendix C-13 for details).

Effects of Stroke

The overall risk ratio for effects of stroke was statistically significantly elevated (risk ratio = 3.79, 8 observed and 2.1 expected, 99% CI = 1.22, 8.80). The stratum-specific risk ratio estimates for stroke are presented in Appendix C-14. No cases were observed in the Dioxin Subregistry for those younger than 35 years of age or older than 64 years of age. Excesses were present for both males (O/E = 9.23 based on five cases) and females (O/E = 7.09 based on three cases) aged 35 through 64 years.

Ulcers, Gall Bladder Trouble, and Stomach or Intestinal Problems

The results for these conditions, namely, ulcers, gall bladder trouble, and stomach or intestinal problems, indicated that the number of cases observed in the Dioxin Subregistry were not statistically significantly different from the number expected based on NHIS rates (details appear in Appendix C-15). The overall estimated risk ratio was 1.27, while those for males and females were 1.47 and 1.11, respectively.

Urinary Tract Disorders, Including Prostate Trouble

Statistically significant excesses were observed both overall (risk ratio = 3.51, 12 observed versus 3.4 expected, 99% CI = 1.45, 7.07) and for females (risk ratio = 5.56, 8 observed and 1.4 expected, 99% CI = 1.79, 12.91). The sex and age stratum risk ratio estimates for urinary tract disorders are given in Appendix C-16. Fourfold and greater excesses were present in females in the 18 through 34 years of age (3 observed and 0.3 expected) and 65 years of age or older (3 observed, 0.2 expected) groups.

SUMMARY

In summary, the results suggest increased reporting by the registrants for the health outcomes anemia and other blood disorders, and stroke. Although the number of all types of cancers is increased there is no one site that predominates. The increases found for skin rashes and urinary tract disorders are more difficult to interpret because of the differential in the wording of the questions for the two data collection instruments.

SECTION 5

COMPARISON OF DIOXIN SUBREGISTRY FOLLOWUP (1 AND 2) DATA AND NATIONAL DATA

REGISTRANT DESCRIPTIVE DATA

There were 250 members enrolled on the Dioxin Subregistry Baseline file: 246 living and 4 deceased. At the time of the first followup (Followup 1), 221 Baseline members participated and there were 5 deceased (1 additional person since Baseline) members; at the time of the second followup (Followup 2), 203 Followup 1 members participated and there were 5 deceased (no additional deaths) members. The results for the recontacts of registrants at each Followup are detailed in Table 5-1. As discussed previously, a death certificate was obtained for the additional deceased member. However, due to the small sample size, the deceased component of the population was not included in the Baseline or the Followup statistical analyses and is not discussed further in this report. Table 5-2 contains information on the sex and age distribution of the registrants participating in the first two Dioxin Subregistry Followup activities. Information from all sites is included in the table.

Table 5-1.—Summary of recontacts of registrants at Followups 1 and 2.

Recontact Outcome	Followup 1		Followup 2
	N	(%)*	N	(%)*
Completed interview, subject living	221	(90)	203	(92)
Completed interview, subject deceased	1	(<1)	0	(0)
Refusal, no data	9	(4)	8	(8)
Refusal, some data	1	(<1)	1	(<1)
Unable to contact	11	(4)	8	(4)
Unavailable during interview period	2	(<1)	0	(0)
Other	1	(<1)	1	(<1)
Total from previous data collection	246	(100)	221	(100)

*Percent of total population recontacted.

Table 5-2.—Summary of current registrants (living) and those lost to followup.

Age at Baseline	Followup 1 (15 months)				Followup 2 (9 months)
	N (%)*		Loss (%)†		N (%)*		Loss (%)†
£17 Years All Males Females	26 13 13	(12)	7	(21)	25 12 13	(12)	1	(4)
18-24 Years All Males Females	24 14 10	(14)	4 2 2	(14)	20 11 9	(10)	4 3 1	(17)
25-44 Years All Males Females	95 46 49	(43)	8 5 3	(8)	86 41 45	(42)	9 5 4	(9)
45-64 Years All Males Females	60 36 24	(27)	2 1 1	(3)	59 23 36	(29)	1 0 1	(2)
³65 Years All Males Females	16 8 8	(7)	3 1 2	(16)	13 7 6	(6)	3 1 2	(19)
Total All Males Females	221 117 104	(100)	25 13 12	(10) (10) (10)	203 107 96	(100)	18 8 10	(8) (7) (9)

*N(%) = Number in sex-age category (percent of total current Followup population

in category).

†Loss(%) = Number lost from previous data collection (percent of previous age-sex

category lost).

Similar to Baseline, 47% of the registrants participating in the Followup data collections were females. At Baseline, approximately 42% of the registrants were from 25 through 44 years of age; this percentage remained relatively constant over the Followups. At Baseline, 13% were under the age of 18 years; this group-less than 18 years of age at Baseline-comprised 12% of the Followup populations.

Exposure ended or occurred before 1985 and Baseline information was collected in 1989; this precluded any registrant's being less than 8 years of age at the first Followup and less than 9 years of age for the second Followup.

RATIONALE FOR THE COMPARISON OF THE

DIOXIN SUBREGISTRY FOLLOWUP DATA WITH NATIONAL DATA

This section includes comparisons of Dioxin Subregistry Followup 1 and Followup 2 data with data from national surveys. As discussed in the previous section, these comparisons are consistent with the Registry objectives and goals as stated in the Policies and Procedures Manual (1). The results of the comparison analyses provide a preliminary assessment of the extent to which Dioxin Subregistry members have an excess of adverse health conditions and aid in generating–rather than testing–hypotheses about dioxin exposure and health outcomes.

NATIONAL COMPARISON POPULATIONS

Dioxin Subregistry Followup 1 and 2 data were compared with data obtained from the 1990 and 1991 National Health Interview Surveys (NHIS) (23,31), respectively. The NHIS file created in the year the Subregistry data were collected was used for comparison. This was considered to be the most appropriate NHIS file to use for comparison; however, in-house analyses suggest that the small amount of year-to-year variability in the NHIS files would not have altered the results had the 1990 NHIS file been used for comparison in the analyses. The NHIS data were used for both the demographic and health data comparisons.

As discussed in the previous section, smoking rates for the Dioxin Subregistry Baseline were compared with national rates derived from several sources, one of which was a subset of the 1990 NHIS data file. The 1990 NHIS did include questions about cigarette smoking; however, these questions were administered to only a subset of the NHIS comparison population that was used in the data analyses presented in this section. Therefore, because only limited NHIS smoking data were available (for a subpopulation), smoking could not be used as a factor in the statistical models used for health response rate comparisons.

Selection of NHIS

Subsets of the NHIS data sets were selected as the comparison data for the National Exposure Registry health outcome components. The appropriateness of using the NHIS population as a comparison population was discussed in the previous chapter. Also previously discussed was that although the NHIS and the Registry are both composed of self-reported data, the NHIS information was obtained using face-to-face interviews while the Dioxin Subregistry Followup information was collected using computer-assisted telephone interviewing. It is not known what differences, if any, might have been introduced using telephone interviewing rather than face-to-face interviewing.

Because of the similarity of the questionnaire items for the data collection instruments used by the NHIS and the National Exposure Registry, the NHIS data were appropriate for the calculation of selected projected prevalence and period prevalence figures and for use in exploratory comparisons with Registry data for health outcomes. The weighting factors (15) provided by the National Center for Health Statistics were applied when using the data. Each of the NHIS files included approximately 100,000 persons. The age groups were matched using the age of the registrants at the time of the interview (not the Baseline age).

METHODS OF DESCRIPTIVE VARIABLE COMPARISONS

The NHIS and Dioxin Subregistry Followup samples were compared in terms of four demographic characteristics: sex, age, race, and education level. As discussed earlier, each of these variables, along with cigarette smoking, is a potential correlate of health status. The same statistical procedures implemented for the Baseline data analyses were used for each of the Followup files. A complete discussion of these procedures was presented in the previous chapter.

METHODS OF COMPARING HEALTH OUTCOMES

Question Comparability

Each of the Dioxin Subregistry Followup files and the appropriate NHIS data reporting rates were compared for each health condition. An assessment of the comparability of NHIS and Dioxin Subregistry health condition questions was made in the previous chapter. Summarizing the previous discussion, the health condition questions for the two surveys differed in three respects: restrictions on the source of diagnosis; the time frame of occurrence or treatment; and, in some cases, the wording of the health condition. Comparability of the Dioxin Subregistry and NHIS questions in terms of the phrasing of health conditions was also discussed in the previous chapter (see Table 4-4). However, in this section, for each health condition the impact of the potential sources of variation on the statistical results is discussed.

Source of Diagnosis

The Dioxin Subregistry Followup questions about health conditions specified that the source of diagnosis must be a physician or other medical provider. The NHIS questions did not include any type of qualification concerning the source of diagnosis. Therefore, if all other factors were similar or equal, an increased reporting by NHIS respondents compared with the Dioxin registrants might be expected, particularly for those health conditions commonly self-diagnosed, and further medical care not sought.

Time Frame

The Health Information Section of the Followup questionnaires for the Dioxin Subregistry inquired about diagnosis or treatment of conditions from date of last interview through the date of the current interview ("Has a physician or other medical provider ever told you/SUBJECT that you/he/she had or treated you/SUBJECT for ... [condition]?"). A specific time frame (the time since the last interview) was used for all questions for each Followup; 15 months for Followup 1 and 9 months for Followup 2. As was done at baseline, respondents who reported positively to this question were then asked whether they (subject) were ever treated for the condition, when they (subject) were first treated for the condition within this time frame, and whether they (subject) were currently being treated for the condition.

The NHIS questionnaire used three different time frames; depending on the condition, respondents were asked if they had ever had, had within the past year, or currently had [have] (at the time of interview) the condition. The time frame for each Registry health condition was standardized to make the NHIS and Dioxin Subregistry rates directly comparable. Table 5-3 provides a comparison of NHIS and Dioxin Subregistry questions in terms of the time frame for each health condition.

One NHIS health condition question was asked in the time frame "have you ever had": the effects of a stroke. Time frames for the Subregistry Followups were made compatible with the NHIS time frame using cumulative information for each registrant: "have you ever had" information from the previous data file(s) plus "have you had since the last interview" of current file (Followup 1 included Baseline data; Followup 2 included the information for Followup 1 also) for these health outcomes.

For the remaining health conditions, the time frame standardization scheme used (as described in the following paragraphs) left the potential for a lower rate of reporting by the Dioxin Subregistry participants. Twelve of the NHIS questions were asked in the time frame "within the past 12 months" (see Section 4 for details on heart disease outcome). In the Dioxin Subregistry Followups, a health condition was defined as occurring "since the last interview"- 15 months for Followup 1, 9 months for Followup 2. The rates for NHIS were calculated based on a 12-month period of time and the response rate was multiplied by the appropriate factor to make time frames comparable to the registry (15/12 times the 12-month rate for Followup 1, 9/12 times the 12-month rate for Followup 2).

There were three health conditions in the NHIS questionnaire that were queried in the time frame "do you now have". These conditions were speech impairment, hearing impairment, and mental retardation. The time frame for the comparable Dioxin Subregistry Followups was modified by counting only registrants who reported that they were "currently receiving treatment" for one of these three conditions. Again, if all other factors were similar or equal, an increased reporting by the NHIS respondents when compared with the Dioxin registrants would have been expected.

Statistical Analysis of Health Data

As for the Baseline analyses, standardized (age and sex) risk ratios were computed for each Followup for each health condition. These ratios serve as an estimate of relative risk. In this case, the expected number of events for a particular sex-age stratum was computed by applying the sex-

Table 5-3.—Comparison of time frames for health condition questions.

Conditions	NHIS* Time Frame	NHIS* Modified Time Frame	Dioxin Followup Time Frame
Stroke	'Ever had'	'Ever had'	For F1, Cumulative of 'Ever had' at Baseline or 'Had since last interview' For F2, add F1 information plus F2 numbers
Cancer, rash, anemia,kidney disease, urinary tract disorders, ulcer, liver problems, asthma, respiratory problems and allergies, diabetes, arthritis, hypertension	'In the last 12 months'	12 month rate times 15/12 (Followup 1) or 9/12 (Followup 2)	Since last interview F1 - 15 months F2 - 9 months
Speech impairment, hearing impairment, mental retardation	'Now have'	'Now have'	'had since last interview' and 'currently have'

*National Health Interview Survey.

age-specific prevalence or period prevalence rate from the NHIS to the corresponding sex-age-specific denominator of the Dioxin Subregistry Followup files. Confidence intervals (CIs) (99%) for the risk ratios were generated using exact methods, with the observed counts assumed to follow the Poisson distribution (27). As for Baseline, the sparseness of the data precluded a detailed statistical analysis of the sex-, age-, and sex-age-specific observed/expected (O/E) ratios. For conditions in which the observed and expected counts were considered to be sufficiently large, exact CIs similar to those mentioned previously were computed for the sex-specific O/E ratios. No adjustments were made for multiple comparisons.

As was done for the Baseline analysis, the complex sampling design of the NHIS was accounted for when computing rates (15). Numerators for a given sex-age stratum were computed by summing the cross product of the "condition weight" and the "basic final weight" for people who were asked the appropriate "condition list" and responded positively for the condition of interest. Denominators were obtained from the NHIS "person" records by summing the "basic final weight" for all people in a particular stratum.

RESULTS OF DESCRIPTIVE COMPARISONS

This section provides a discussion of the comparability of descriptive data from the Dioxin Subregistry file and the NHIS file.

Demographics

Race

In the Dioxin Subregistry Baseline sample, 98% (n = 241) of the subjects selected their race as white. This did not change appreciably for the Followups. As discussed earlier in Section 4, because of the small number of nonwhites in the Subregistry population compared with the NHIS population, only whites are included in the NHIS comparison population used in this report.

Sex

Table 4-5 provides comparisons of the proportion of males within age categories for the Dioxin Subregistry Baseline and the NHIS populations. Similar comparisons of the Followup files with the appropriate NHIS files yielded the same results; no statistically significant differences were found in any of the age categories examined.

Age

The age distributions of the Dioxin Subregistry Baseline file and the NHIS file are presented in Table 4-6. Similar comparisons using the appropriate NHIS files and age groups were carried out for each Followup file. The distributions were compared statistically through chi-squared goodness-of-fit tests for each sex-specific group; the results were very similar to those for Baseline analyses. For females and males, the age distribution of the Subregistry Followup files was not statistically significantly different from that of the NHIS.

Education

The education distributions of the Dioxin Subregistry Baseline and the NHIS populations are presented in Table 4-7. Only those subjects 19 years of age or older were included. These distributions were compared statistically through chi-squared goodness-of-fit tests for each sex-specific subgroup. This was repeated for the Followup files using the appropriate NHIS files and age groups. The results were similar to those of the Baseline for each Followup file. The distribution for males was statistically significantly different from that of the NHIS; the Subregistry population contained substantially more people with less than 12 years of education and substantially fewer college-educated people than expected based on NHIS figures. For females, education distribution for each of the Subregistry Followup files was marginally statistically significantly different from that of the appropriate NHIS files.

Cigarette Smoking

Table 4-8 provides smoking rates for registrants 18 years of age or older. To be classified as "current" or "ever" smokes, registrants had to have smoked at least 100 cigarettes in their lifetime. The rates of smoking were high when compared with the national rates, particularly for women. A detailed discussion of smoking rates was presented in Section 4. In summary, the conclusion reached was, based on a comparison of smoking rates from the Dioxin Subregistry and national sources, the possibility exists that smoking is a factor, particularly for females, when comparing reported health outcomes from the Dioxin Subregistry and 1989 NHIS files. Smoking status must be considered when interpreting findings for outcomes for which it might play a role (32).

RESULTS OF HEALTH OUTCOME COMPARISONS

The risk ratios for each health outcome for Followups 1 and 2 are displayed in Tables 5-4 and 5-5, respectively. A value greater than one indicates an excess of positive responses in the Dioxin Subregistry relative to the number expected based on NHIS rates. The risk ratios for several health conditions were statistically significantly elevated at the p = 0.01 level. These included all cancers (Followup 2), skin rashes (Followups 1 and 2), stroke (Followup 2), and urinary tract disorders (Followups 1 and 2). Statistically significant deficits in reporting by the Dioxin Subregistry population were observed for hearing impairment at Followups 1 and 2.

In addition to the overall risk ratio, the sex, age, and sex-age O/E ratios are presented in Appendix D for Followup 1 and Appendix E for Followup 2. Sparse data precluded a statistical evaluation of all age- and sex-age-specific ratios. When the observed and expected counts were considered to be sufficiently large, exact 99% CIs were generated for the sex-specific ratios. It should also be noted that the small observed and expected counts in many of the sex-, age- and sex-age-strata also made observational interpretation of the data somewhat tenuous. That is, the O/E ratio might have been quite large, yet its components so small that any change in the numerator (the observed count in the Subregistry) would substantially alter the ratio. In Tables 5-6 and 5-7, the statistically significant results for Followup 1 and Followup 2 subgroups are shown for each health condition. A comparison of the results for Baseline, Followup 1, and Followup 2 are shown in Table 5-8. A discussion of these results follows. It must be kept in mind that the time frames vary for each file.

Also included in the discussion is information on consistency of reporting by individuals; that is, to determine whether the same people reported the same condition(s) repeatedly. This would be expected for some conditions and not for others, and serves as an indicator of reporting consistency within the population.

Table 5-4.—Summary of risk ratios for Followup 1.

Condition	Observed (Dioxin)	Expected (NHIS)	Risk Ratio	99% CI*
Statistically Significantly Elevated Risk Ratios†
Skin rashes	35	20.04	1.75	1.08, 2.66
Urinary tract disorders	14	4.12	3.40	1.51, 6.51
Statistically Significantly Lowered Risk Ratios†
Hearing impairment	3	30.06	0.10	0.01, 0.36
Statistically Nonsignificant Risk Ratios†
Arthritis	33	48.79	0.68	0.41, 1.04
Respiratory allergies	19	30.64	0.62	0.32, 1.09
Asthma, emphysema	21	25.01	0.84	0.44, 1.44
Diabetes	8	6.66	1.20	0.39, 2.79
Kidney disease	7	4.14	1.69	0.49, 4.14
Liver	2	0.94	2.13	0.11, 9.87
Mental retardation	0	1.68	0.00	0.00, 2.74
Speech impairment	1	1.93	0.52	0.00, 3.84
Stomach problems	20	22.48	0.89	0.46, 1.54
Anemia and other blood disorders	9	3.74	2.40	0.84, 5.34
Cancer	5	2.98	1.68	0.36, 4.74
Stroke	8	3.11	2.57	0.83, 5.98
Hypertension	29	32.13	0.90	0.53, 1.43

*CI-Confidence interval.

†p = 0.01.

Table 5-5.—Summary of risk ratios for Followup 2.

Condition	Observed (Dioxin)	Expected (NHIS)	Risk Ratio	99% CI*
Statistically Significantly Elevated Risk Ratios†
Cancer	7	1.70	4.12	1.20, 10.09
Skin rashes	24	10.70	2.24	1.24, 3.72
Stroke	8	1.61	4.98	1.60, 11.56
Urinary tract disorders	17	2.31	7.36	3.57, 13.33
Statistically Significantly Lowered Risk Ratios†
Hearing impairment	3	16.27	0.18	0.02, 0.68
Statistically Nonsignificant Risk Ratios†
Arthritis	35	28.08	1.25	0.77, 1.90
Asthma, emphysema	12	14.61	0.82	0.34, 1.65
Diabetes	5	4.40	1.14	0.24, 3.21
Kidney disease	2	2.01	0.96	0.05, 4.46
Liver	1	0.53	1.91	0.10, 14.20
Mental retardation	0	0.87	0.00	0.00, 5.31
Speech impairment	0	1.29	0.00	0.00, 3.58
Stomach problems	18	13.61	1.32	0.68, 2.36
Anemia and other blood disorders	3	1.90	1.58	0.18, 5.77
Respiratory allergies	22	17.93	1.23	0.66, 2.08
Hypertension	29	18.58	1.56	0.92, 2.47

*CI-Confidence interval.

†p = 0.01.

Table 5-6.—Statistically significant (p £ 0.01) subgroup risk ratios for Followup 1.

Condition	Sex	Age (Years)*	Number Observed	Number Expected†	Risk Ratio	99% CI§ (Exact)
Anemia and other blood disorders	Male All	All 55-64	5 3	0.38 0.26	13.13 11.69	2.83, 37.15 1.32, 42.78
Hearing impairment	Female All Male All All Male Male	All All All 35-44 55-64 45-54 55-64	1 3 2 0 0 0 0	9.30 30.06 20.75 5.30 6.71 4.67 5.33	0.11 0.10 0.10 0.00 0.00 0.00 0.00	0.00, 0.80 0.01, 0.36 0.00, 0.45 0.00, 0.87 0.00, 0.69 0.00, 0.98 0.00, 0.86
Urinary tract disorders	All Female All All Male Female	All All 25-34 55-64 55-64 18-24	14 7 4 5 4 2	4.12 1.43 0.32 0.75 0.59 0.09	3.40 4.91 12.32 6.66 6.84 23.08	1.51, 6.51 1.43, 12.01 2.07, 38.78 1.44, 18.86 1.15, 21.53 1.19, 107.03
Skin Rash	All	All	35	20.04	1.75	1.08, 2.66
Arthritis	All	65+	2	9.77	0.21	0.01, 0.95

*Age grouping reflects Baseline age and not current age. Current age is 15 months greater.

†Standardized to 15-month time frame.

§CI-Confidence interval.

Anemia or Other Blood Disorders

The time frame for this health condition at Baseline was the last 12 months. At Baseline, the overall risk ratio of 3.54 (12 observed versus 3.9 expected, 99% CI = 1.46, 7.12) indicated a statistically significant increase in reporting for the Dioxin Subregistry population over that expected based on the NHIS reporting rate. There was an increase in overall reporting, but not a statistically significant increase in reporting for either Followup 1 (O/E = 2.40, 9 observed versus 3.7 expected, 99% CI = 0.84, 5.34) or Followup 2 (O/E = 1.58, 3 observed versus 1.9 expected, 99% CI = 0.18, 5.77). The sex-, age-, and sex-age-specific estimated risk ratios for anemia are detailed in Appendix D-1 for Followup 1 and in Appendix E-1 for Followup 2. As was the case at Baseline, a statistically significant excess in reporting was seen for males for Followup 1 (O/E = 13.13, 5 observed and 0.4 expected, 99%  CI = 2.83, 37.15). For Followup 2, similar increases were found but were not

Table 5-7.—Statistically significant (p £ 0.01) subgroup risk ratios for Followup 2.

Condition	Sex	Age*	Number Observed	Number Expected†	Risk Ratio	99% CI§ (Exact)
Hearing impairment	All Male	All All	3 1	16.27 10.83	0.18 0.90	0.021, 0.000,	0.680 0.690
Rash	All All	All 35-44	24 9	10.70 2.99	2.24 3.01	1.24, 1.05	3.72 6.68
Stroke	All All Male	All 45-54 All	8 3 5	1.61 0.33 0.89	4.98 9.00 5.61	1.61, 1.01, 1.21	11.56 32.94 15.88
Urinary tract problems	All Male Female All All Male Female	All All All 45-54 55-64 55-64 45-54	17 8 9 6 4 4 4	2.31 1.53 0.78 0.42 0.57 0.48 0.06	7.36 5.24 11.49 14.44 7.05 8.27 73.10	3.57, 1.68, 4.00, 3.70, 1.18, 1.39, 12.28	13.33 12.16 25.53 37.70 22.20 26.03 230.14
Cancer	All	All	7	1.70	4.12	1.20,	10.09

*Age grouping reflects Baseline age, not current age. Current age is 9 months greater than Followup 1 age, 24 months greater than Baseline age.

†Based on 9-month time frame.

§CI-Confidence interval.

statistically significant (the data were very sparse). Similarly, there was a statistically significant increase in reporting for both Baseline and Followup 1, but the increase was not statistically significant for Followup 2 (see Table 5-6).

There were no registrants who reported positively for this condition at all three data collections. Only 5 of the 30 registrants who reported at Baseline of ever being told they had or were treated by a health care provider for this condition reported positively a second time. Four of the nine cases reported at Followup 1 were first time reports; two of the three cases reported at Followup 2 were first time reports.

Table 5-8.—Summary of statistically significant* results (risk ratios, total population) for Baseline, Followup 1, and Followup 2.

Condition	Baseline (ever or 12 months)†	Followup 1 (15 months)	Followup 2 (9 months)
Statistically Significantly Elevated Risk Ratios
Anemia and other blood disorders	X§
Skin rashes	X	X	X
Urinary tract disorders	X	X	X
Cancer (all)	X		X
Stroke	X		X
Statistically Significantly Lowered Risk Ratios
Hearing impairment	R¶	R	R
Respiratory allergies	R
Statistically Nonsignificant Risk Ratios
Arthritis	**
Asthma, emphysema
Diabetes
Kidney disease
Liver
Mental retardation
Speech impairment
Stomach problems
Hypertension

*p = 0.01

†Indicates time frame used for comparisons with National Health Interview Survey.

§X indicates Subregistry reporting rate statistically greater.

¶R indicates NHIS reporting rate statistically greater.

**Blank indicates no statistical difference in reporting rates.

Arthritis, Rheumatism, or Other Joint Disorders

At Baseline, the time frame for these conditions was the last 12 months. For Baseline, the overall risk ratio was less than one, indicating fewer positive reports by the Subregistry population than expected; the same pattern prevailed for Followups 1 and 2. The sex-, age-, and sex-age-specific estimates for arthritis for Followup 1 are shown in Appendix D-2 and for Followup 2 are shown in Appendix E-2. Most of the sex-age-specific ratios were less than one, indicating that the reported prevalence of arthritis was generally lower in the Dioxin Subregistry data than expected based on the NHIS prevalence rates.

As would be expected for these conditions, there were a number of registrants who repeatedly reported positively. Of the 35 registrants reporting positively at Followup 2, 20 had reported positively at all reporting periods; 5 were first time reports.

Asthma, Emphysema, or Chronic Bronchitis

At Baseline, the time frame for these conditions was the last 12 months. The estimated Baseline overall risk ratio was decreased when compared with NHIS; however, the decrease was not statistically significant. This was true for both Followups 1 and 2. The stratum-specific risk ratio estimates are given in Appendices D-3 and E-3 for Followups 1 and 2, respectively.

Of the 12 positive reports at Followup 2, 8 were third-time positive reports; 1 was new; and the others were second-time positive reports.

Cancer

The overall ratio for all cancers (those for which the date of first treatment was within the last 12 months for a registrant currently being treated) was statistically significantly elevated at Baseline at the p = 0.01 level (O/E = 3.56, 99% CI = 1.14, 8.27). There were 8 reported cancer cases (3 thyroid, 1 bladder, and 4 skin); 2.2 were expected based on the NHIS reporting rates. For Followup 1, there were 5 reported cancers (3 skin, 1 colon, and 1 brain). One skin cancer and the colon cancer were new registrants reporting; the brain cancer was reported by a registrant reporting a thyroid cancer at Baseline. At Followup 2, 7 cancers were reported (4 skin, 1 prostate, 1 thyroid, and 1 uterine). Two registrants reporting skin cancers and one reporting uterine cancer had not responded positively at either Baseline or Followup 1 (see Tables 5-9 and 5-10). For both populations, the relative rates were <1 for all cancers; statistically significantly <1 for Followup 2. Appendices D-4 and E-4 show the results for the "all cancer" outcome using 9-month- and 15-month-period reporting rates for Followups 1 and 2, respectively. It should be noted that the data were very sparse for this outcome and the types of cancer reported were varied.

Diabetes

At Baseline, the time frame for this condition was the last 12 months. Neither the Baseline overall risk ratio nor the sex-specific ratios were statistically significantly elevated for diabetes; similar results were found for both Followups 1 and 2. Age and sex subgroup details appear in Appendix D-5 (Followup 1) and Appendix E-5 (Followup 2).

Of the five cases reported at Followup 2, only one was new; the other four had been reported each prior period. Also noteworthy is that all respondents were above the age of 35 years.

Table 5-9.—Types of cancer in Dioxin Subregistry Followup 1 reported by age group and sex (time frame is last 15 months).

Age (years)	Type of Cancer*
	Male	Female
8-17
18-24
25-34
35-44
45-54	Skin (1)
55-64	Skin (1) Colon (1)
³65		Skin (1) Brain (1)

*Numbers in parentheses represent number of cases.

Hearing Impairment

Hearing impairment is one of the health outcomes whose responses are considered in the time frame currently being treated. An overall risk ratio statistically significantly <1 found at Baseline was also noted in both Followups (Followup 1 O/E = 0.10, 99% CI = 0.01, 0.36; Followup 2 O/E = 0.18, 99% CI = 0.02, 0.68). This reversal (seen for both males and females) is, as discussed previously, predictable in that hearing impairment is commonly self-diagnosed, and the fact that Subregistry cases must have been confirmed or treated by a health care provider and NHIS cases might result in substantially less reporting in the Dioxin Subregistry relative to NHIS. The stratum-specific risk ratio estimates (all are <1) for hearing impairment are presented in Appendices D-6 and E-6.

Of the three cases reported at Followup 2, two of them were reported during all data collection efforts.

High Blood Pressure (Hypertension)

The estimated risk ratios were not statistically significantly elevated for reporting overall for Followup 1 (O/E = 0.90, 29 observed versus 32.1 expected, 99% CI = 0.53, 1.43) or Followup 2 (O/E= 1.56, 29 observed and 18.6 expected, 99%CI = 0.92, 2.47). The stratum-specific risk ratio estimates for hypertension are furnished in Appendices D-7 and E-7.

Table 5-10.—Types of cancer in Dioxin Subregistry Followup 2 reported by age group and sex (time

frame is last 9 months).

Age (years)	Type of Cancer*
	Male	Female
8-17
18-24
25-34
35-44		Uterus (1)
45-54	Skin (1)
55-64	Skin (2) Prostate (1)
³65		Skin (1) Thyroid (1)

*Numbers in parentheses represent number of cases.

Kidney Disease

The overall risk ratio was not statistically significantly different from unity for Baseline or either Followup. The sex-, age-, and sex-age-specific risk ratio estimates for kidney disease are presented in Appendices D-8 and E-8 for Followups 1 and 2, respectively. The data were very sparse.

Of the seven cases reported at Followup 1, four were new reports; both of the two cases reported at Followup 2 had been previously reported.

Liver Problems

The overall risk ratio was not statistically significantly different from 1 for any sex or age group for Baseline or Followups 1 and 2. The stratum-specific ratios for liver problems for Followups 1 and 2 are given in Appendices D-9 and E-9, respectively. The data were very sparse for all three data collection periods, precluding meaningful analyses and making interpretation tenuous.

Mental Retardation

The sparseness of the data for this condition made analyses and interpretation impossible for any data collection period. The summaries for Followup 1 are shown in Appendix D-10 and for Followup 2 in Appendix E-10.

Skin Rashes, Eczema, or Other Skin Allergies

There was a statistically significant increase in reporting for these conditions together at Baseline by the Dioxin Subregistry population (O/E = 1.81, 29 reported versus 16.0 expected, 99% CI = 1.06, 2.87); at Followup 1 (O/E = 1.75, 35 observed versus 2.0 expected, 99% CI = 1.08, 2.66); and at Followup 2 (O/E = 2.24, 24 observed and 10.7 expected, 99% CI = 1.24, 3.72). Most of the sex-age specific ratios were >1 for each of the three databases (see Appendices C-11, D-11, and E-11). Individuals in the 35 through 44 years of age group had the highest risk ratios for all three periods.

Of the 24 positive reports at Followup 2, 10 had registrants consistently reporting (both Baseline and Followup 1) being treated for this condition, 4 were new, and the remainder had reported positively at another time.

Other Respiratory Allergies or Problems, Such as Hay Fever

The overall estimated risk ratio for respiratory allergies was statistically significantly less than 1.0 (O/E = 0.48, 12 observed but 25.5 expected, 99% CI = 0.20, 0.96). Although <1, the Followup 1 risk ratios were not statistically significantly different from 1 (Followup 1, O/E = 0.62, 19 observed versus 30.6 expected, 99% CI = 0.32, 1.09). For Followup 2, the risk ratio was greater than but not statistically different from 1 (O/E = 1.23, 22 observed versus 17.93 expected, 99% CI = 0.66, 2.08). With few exceptions, the age-specific risk ratio estimates were less than unity (details for Followups 1 and 2 are shown in Appendices D-12 and E-12, respectively).

Of the 22 cases reported for Followup 2, 5 were reported at Baseline and Followup 1; 7 had not been previously reported.

Speech Impairment

For speech impairment, there was only one positive response to "currently being treated" in both the Dioxin Subregistry Baseline and Followup 1 (Appendix D-13); none were reported for Followup 2 (Appendix E-13), thus precluding meaningful statistical analyses.

Stroke

This condition was assessed in the time frame "ever had". The method of calculating the time frames for the Followups was discussed earlier. The overall risk ratio was statistically significantly elevated for Baseline (O/E = 3.79, 99% CI = 1.22, 8.80) and Followup 2 (O/E = 4.98, 99% CI = 1.60, 11.56) based on the same 8 cases. Although not statistically significant, the risk ratio was elevated for Followup 1 (O/E = 2.57, 99% CI = 0.83, 5.98). The stratum-specific risk ratio estimates for stroke are presented in Appendices D-14 (Followup 1) and E-14 (Followup 2). No cases were observed in the Dioxin Subregistry for those less than 35 years of age or more than 64 years of age at Baseline. Excesses were present for both males and females, but it should be noted that the outcome remains a rare event.

Ulcers, Gall Bladder Trouble, and Stomach or Intestinal Problems

The results for ulcers (details appear in Appendices D-15 and E-15) indicated that the number of cases observed in the Dioxin Subregistry were not statistically significantly different from the number expected based on NHIS rates for either Followup (as for the Baseline). Most estimated risk ratios were close to or less than 1.

Of the 18 positive reports at Followup 2, 5 had not previously reported being treated; 6 reported being treated at all 3 reporting times.

Urinary Tract Disorders, Including Prostate Trouble

Statistically significant excesses were observed overall at Baseline (O/E = 3.51, 12 observed versus 3.4 expected, 99% CI = 1.45, 7.07) and both Followups (Followup 1, O/E = 3.40, 14 observed and 4.1 expected, 99% CI = 1.51, 6.51 and Followup 2, O/E = 7.36, 17 reported and 2.3 expected, 99% CI = 3.57, 13.33). The female subgroup reporting was statistically increased at Baseline and Followups 1 and 2; males at Followup 2 only. The stratum-specific risk ratio estimates for the Followup files for urinary tract disorders are given in Appendices D-16 and E-16. The statistical significance for specific age- and sex- and age-groups varied over databases (see Tables 5-5 and 5-6). The total numbers were small and ratios changed considerably with small changes in the number of cases.

Of the 17 cases reported at Followup 2, only 6 had been reported uninterrupted; 6 had not been reported at any previous data collection. Therefore, the uniform statistically significant increases found across data files and age groups did not appear to be repeated reporting by a certain subpopulation.

SUMMARY

The excess reporting of anemia and other blood disorders found at Baseline did not occur at Followups 1 or 2. The excess reporting of skin rashes and urinary tract disorders occurred at Baseline and Followups 1 and 2. The excess reporting of all cancers and stroke was seen at Followup 2 and not Followup 1. The consistency in reporting is noteworthy and, having occurred over a considerable time span, gives increased importance to the results found.

SECTION 6

DISCUSSION

A key purpose of the Dioxin Subregistry is to facilitate followup and investigation of adverse health outcomes in a cohort of exposed individuals. This is accomplished by assembling sufficient information on exposed people to determine if there is an excess reporting of adverse health conditions for registrants when compared with a national sample. This information is used to generate hypotheses for future testing. To date, this purpose has been pursued by creating and comparing Dioxin Subregistry data about health conditions with National Health Interview Survey (NHIS) data. Health, demographic, and occupational information was collected on 250 dioxin-exposed persons for Baseline reporting, 226 for the first follow-up period (Followup 1), and 208 for the second follow-up period (Followup 2). The analysis of the mortality data is not included in this report.

Several sources of potential biases in the Dioxin Subregistry population reporting rates were identified. The participation rate of eligible persons who were located at the time of Baseline data collection was 91%, with 96% participation for Followup 1 and 96% participation for Followup 2. Such a high participation rate would eliminate bias in the data that might have been associated with nonresponse.

Pursuing sources of potential bias further, the Subregistry and NHIS questions about health conditions shared important similarities, but differed in two ways: (1) a Subregistry restriction on the source of diagnosis and treatment, and (2) the wording of some of the questions about health conditions. Concerning the source of diagnosis and treatment, the Dioxin Subregistry questions specified that the source of diagnosis or treatment for a positive response to a health question must be a "physician or other medical provider". This restriction was added to each Subregistry question about health conditions in an effort to minimize biased reporting by registrants whose health awareness might have been heightened by their participation in a previous health study or site activities. The inclusion of this qualifier had the potential to reduce the rates of reporting for the Subregistry when compared with the NHIS rates, all other factors being similar or equal, and modulate increased reporting due to bias. Some conditions are more commonly self-diagnosed and these would predictably be reported at a higher rate by the NHIS participants; the results were consistent with that prediction. There was a decrease in reporting by the registrants for the conditions arthritis, hearing impairment, and respiratory allergies-conditions often self-diagnosed. There was one exception to the predicted increased reporting rates by NHIS participants for commonly self-diagnosed problems-the reporting of skin problems. In this case, there was an increased reporting by the total Dioxin Subregistry population for all three reporting periods (Baseline, Followup 1, and Followup 2).

The comparability of the wording of Dioxin Subregistry and NHIS health conditions was addressed in Section 4. Nine of the health condition questions matched exactly or very closely and eight others were considered similar. However, when the questions did not match exactly, all other factors being similar or the same, it was likely the dissimilarity would have resulted in decreased reporting by the Dioxin Subregistry population, with the possible exception of urinary tract disorders. Also as discussed previously, for those questions asked by NHIS in the 12-month time frame there was the potential of not ascertaining complete registry response. Unlike the NHIS, the Subregistry would have missed those who were treated within the past year but it was not first treatment or they were not currently being treated. It was expected that the file refinements necessary to make the NHIS and Dioxin Subregistry files compatible would result, all other factors being consistent, in lower reporting rates for the Dioxin Subregistry population. The implications of health condition comparability are addressed further in the discussion of health outcomes.

ENVIRONMENTAL DATA

As is discussed at length in Section 3, the environmental data available were collected and evaluated; however, the limitations of the data merit reiteration. The samples were not taken for the purpose of quantifying personal exposures over time. Most of the environmental data represent multiple samples taken at various locations at each site for the purpose of quantifying levels of soil contamination. The maximum soil levels reported for the four sites in the Dioxin Subregistry ranged from 740 parts per billion (ppb) to 33,000 ppb. It should also be noted that the potential for exposure also varied with the type of site; that is, the site was either a residential area or a horse arena. The activity(ies) leading to exposure would, therefore, vary with the type of site. Regardless, the data served the Registry's purpose in that they provided the basis for the selection of participants in the four health studies from which the Dioxin Subregistry population was drawn.

When attempting to assess the health effects potentially related to exposure to dioxin in soil, the bioavailability of the compound must be considered. The bioavailability varies by region; for example, the bioavailability of dioxin in soil samples from New Jersey and Missouri differed (33,34), with dioxin from soil in Missouri being significantly more bioavailable. Also, dioxins are stable in the environment. In fact, all available evidence from information on contaminated soils, such as that which was found in Seveso, Italy, and Times Beach, Missouri, suggests an extremely long half-life-greater than 10 years-for dioxin in soil (35). Higher chlorinated dioxins are selectively dechlorinated photolytically, leaving a more stable planar molecule of dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin, which is also the most toxic (36).

HEALTH OUTCOMES

Dioxin is distributed equally among the fat and liver of mammals and, to a lesser extent, in the kidneys; it is eliminated via the feces (37). Dioxin also has a long half-life in humans. Workers exposed to dioxin in chemical process accidents in the 1950s and 1960s still had high concentrations measurable in their body fat in the 1980s. Some veterans exposed to Agent Orange in Vietnam continue to have relatively high body burdens of dioxin 20 years after their exposure (38). Limited data indicate that the half-life for loss of dioxin in humans could be 5.8 to 7.1 years (39,40).

Little is known about the absorption of dioxin in humans. Poiger and Schlatter (40) found >87% gastrointestinal absorption in a volunteer who consumed dioxin in corn oil; transpulmonary absorption is believed to be similar to that observed following oral exposure. Following dermal exposure, most dioxin remains in the stratum corneum layer (41).

Values for dioxin in blood serum ranged from 0 to 618 parts per trillion (ppt) in project Ranch Hand personnel; the median value was 12.8 ppt. The median value of the comparison group was 4.2 ppt (42). In the general U.S. population, the background level of dioxin in adipose tissue ranged from 5.38 ppt (1.9 ppt in children less than 14 years of age) to 9.40 ppt in adults over 40 (43). Tissue levels of dioxin up to 56,000 ppt on a lipid basis have been observed in children of Seveso. These children have shown either mild chloracne or no adverse health effects (44). Adipose tissue analysis of "unexposed" populations suggests that most, if not all, individuals have some body burden of "dioxin equivalents" with wide variation among individuals (45). Also, the partition of dioxin into breast milkfat, while a mode of excretion and detoxification for the lactating female, is not without impact on nursing infants (46-48). This might be of further relevance if the mechanism of action of dioxin is indeed on differentiation and development.

The most striking and controversial observation concerning the toxicology of dioxin is the apparent dichotomy between the results of animal toxicity studies (including those involving nonhuman primates) and experience to date in human studies; that is, the contrast between a large and relatively consistent literature on the experimental aspects and a smaller, inconclusive literature on its epidemiology (49). Present results suggest that males seem to be more sensitive than females to the action of dioxin. Studies in animals have shown that male rats also seem to be more sensitive than females to dioxin as determined by the lethal dose for 50% survival for the group, but Moore (50) has reported an opposite effect in other animals.

In 1984, Kimbrough et al. (51) published a risk assessment for dioxin contamination of residential soil in which cancer and fetotoxicity were among the adverse outcomes of dioxin exposure considered. They stated, "At the daily dose likely to be obtained as estimated above for a soil level of 1 ppb (44.6 picograms [pg] per day), these extrapolations from reproduction studies in subhuman primates appear to suggest a situation of no excess risk in humans. However, at virtually all other estimated levels of daily dose (i.e., under a more rigorous set of assumptions or the higher level of dioxin in soil), one might expect adverse reproductive effects" (51).

Under the current federal guidelines, the U.S. Environmental Protection Agency (EPA) decided that ingesting more than 0.006 trillionths of a gram of dioxin for each kilogram (kg) (2.2 pounds) of body weight daily over an average lifetime might cause one total cancer for each million people. Thus, a man weighing 80 kg, or 176 pounds, is urged not to eat, drink, or breathe more than 0.5 trillionths of a gram of dioxin every day. EPA used the same statistical method to calculate the safe exposure to dioxin to set a safe level in water of 13 parts per quintillion; in the same manner, the Centers for Disease Control and Prevention has established a soil level of 1 ppb (52). These levels are far below the 1 to 3 pg/kg/day that people are estimated to actually be ingesting. Other nations, using different risk assessment models, have calculated the tolerable intake level much higher. Germany uses 1 pg, the Netherlands 4 pg, and Canada and the World Health Organization (WHO) use 10 pg (42).

Molecular biology has shown that the action of dioxin in a cell is receptor mediated. This receptor-mediated action was discovered by Poland et al. (53) when low levels of dioxin were injected into animals and induction of a particular cytochrome P-450 microsomal enzyme that oxygenates substrates, such as the carcinogen benzo[a]pyrene, that accumulate in fatty tissues occurred in a dose-dependent manner. It was noted that other planar chlorinated dioxins, dibenzofurans, and polychlorinated biphenyls (PCBs) elicited a similar, though weaker, response. The mechanism is believed to be classic receptor-mediated transduction, very similar to the way steroid hormones are made in the cells. The receptor was recognized as a soluble intracellular protein and was designated the Ah-for aryl hydrocarbon-receptor (54). The Ah receptor is a specific intracellular macromolecule that mediates dioxin-induced toxicity in vertebrate animals (49). Subsequent research identified another protein, a translocation factor designated as Arnt (for Ah receptor nuclear translocator), necessary for the complex to pass from the cytoplasm into the nucleus (55,56). Once inside the nucleus, several of these complexes attach to a specific sequence on the cell's deoxyribonucleic acid (DNA), distorting the DNA chain and allowing attachment of other binding proteins. These events lead to the transcription of messenger ribonucleic acid that forms the cytochrome P-450 or other enzymes that might be induced by dioxin (42).

Recently, researchers at the National Institute of Environmental Health Sciences (NIEHS) have challenged the receptor-mediated model for dioxin (57). The basis for this controversy is the finding that the model failed to predict that bonding of dioxin to the Ah receptor follows linear kinetics at low doses, which the model allows, but that induction of the Ah receptor by the dioxin-Ah complex does not alter the curve. Binding of dioxin to other liver proteins did not significantly alter the dose-response curve for expression of any of the proteins modeled. Not only was the NIEHS model unable to detect any nonlinearity in cell kinetics, it also indicated that dioxin potentially produces premalignant lesions in the liver.

As discussed in Section 4, the comparisons of Dioxin Subregistry and NHIS data on reported health conditions revealed several statistically significant differences. It should be noted that setting the Type I error (the α level) at £0.01 served to reduce the likelihood of false negative or false positive results. Also of note when considering the analyses and interpreting the results is the small sample size. The results of the morbidity analyses are summarized in Table 6-1 and are discussed in the following section with respect to the relevant literature. As discussed earlier, there was an even greater expectation of increased reporting by NHIS respondents for the group of health outcomes that are many times self-diagnosed without confirmation from a health care provider. The first outcomes discussed-arthritis, hearing impairment, and respiratory allergies-are of this group.

Arthritis, Rheumatism, or Other Joint Disorders

The only statistical difference (risk ratio statistically significantly different from 1) found was that arthritis was reported significantly less often for registrants 65 years of age or older at Followup 1 than for the corresponding NHIS population. It should also be noted that this outcome is one that is commonly self-diagnosed; therefore, some increased reporting would be expected in the NHIS population since the NHIS question did not require diagnosis or treatment by a physician or other health care provider. The time frame for the question was last 12 months.

No studies were located specifically addressing arthritis and dioxin exposure; however, Kimbrough et al. (58) reported two individuals exposed to dioxin in horse arenas in Missouri were diagnosed with arthralgia. Most animal studies have not found musculoskeletal effects (6).

Hearing Impairment

The Dioxin Subregistry population and male subpopulation reported statistically significantly fewer hearing impairments at Baseline and Followups 1 and 2. Although statistically significant differences were found for other subpopulations, the numbers were too small to draw meaningful

Table 6-1.—Summary results of Dioxin Subregistry (Baseline and Followups)-National Health Interview Survey comparison.

Disease Category	Age Groups (Years)
	0-9		10-17		18-24		25-34		35-44		45-54		55-64		³65		All		All	8-17	18-24	25-34	35-44	45-54	55-64	³65
	M	F	M	F	M	F	M	F	M	F	M	F	M	F	M	F	M	F
Arthritis
Baseline
Followup 1																										R
Followup 2
Hearing Impairment
Baseline																	R	R	R
Followup 1											R		R				R	R	R				R		R
Followup 2																	R		R
Respiratory Allergies
Baseline																			R
Followup 1
Followup 2
Stroke
Baseline											X						X		X
Followup 1
Followup 2																	X		X					X
Anemia and Other Blood Disorders
Baseline																	X		X						X
Followup 1
Followup 2																	X								X
Urinary Tract Disorders
Baseline																X		X	X
Followup 1						X							X					X	X			X			X
Followup 2												X	X				X	X	X					X	X

Table 6-1.—Continued.

Disease Category	Age Groups (Years)
	0-9		10-17		18-24		25-34		35-44		45-54		55-64		³65		All		All	8-17	18-24	25-34	35-44	45-54	55-64	³65
	M	F	M	F	M	F	M	F	M	F	M	F	M	F	M	F	M	F
Skin Rashes
Baseline																			X
Followup 1																			X
Followup 2																			X				X
Cancers (all)
Baseline																			X
Followup 1
Followup 2																			X

X-Statistically significant differences, Dioxin Subregistry rate higher.

R-Statistically significant differences, NHIS rate higher.

conclusions. As mentioned previously, this outcome is one for which self-diagnosis is common. The questions on the respective questionnaires were a close match. The time frame for the question was "currently being treated."

Questionnaires of perceived neurological problems in Vietnam veterans potentially exposed to dioxin showed more complaints of hearing loss when compared with those of controls (59); however, some of the reported losses may have been due to exposure to high levels of noise. No other studies specifically addressing hearing impairments and dioxin exposure were located in the literature.

Other Respiratory Allergies or Problems, Such as Hay Fever

Respiratory allergies were statistically significantly lower for the Dioxin Subregistry population overall at Baseline than for the NHIS population. The reporting rates did not differ for Followups 1 or 2. The questions addressing these outcomes are a close match on the respective questionnaires. Again, this is an outcome often self-diagnosed; therefore, the apparent excess in the NHIS population at Baseline might have been due to the lack of a requirement for a physician or other medical provider diagnosis or treatment, or both.

Reports in the literature of respiratory disease following dioxin exposure have been varied. In a 30-year clinical study of 436 workers in Nitro, West Virginia, Suskind and Hertzberg (60) found statistically significantly decreased pulmonary function in smokers even after adjustment for pack years smoked (for current smokers only). In the Missouri Central Listing population, minor pulmonary abnormalities were reported in the high-risk group over the low-risk group (9). These findings were believed to be evidence of a pattern or trend; however, the authors cited small sample size, self-selected populations, and lack of an objective measure of exposure status as limitations. Morphological changes in respiratory tissues have been reported in rats fed dioxin in the diet for 2 years (61).

In a study of Vietnam veterans, Anderson and coworkers (62) reported an elevated proportional mortality ratio (PMR) (2.0) due to pneumonia; however, since the deaths were for the period of 1964 through 1983, the authors felt they could have been related to combat wound complications. PMRs for all respiratory diseases together were not significant (PMR = 1.0) when comparing Vietnam veterans with Vietnam era veterans. In addition, mortality from respiratory disease has not been reported elevated for other studies (63-75).

Other negative findings have also been reported. In the 10 years following the Seveso accident, the mortality due to respiratory disease in individuals aged 20 through 74 years was close to that expected (68). In the Air Force Ranch Hand Study, analyses of pulmonary disease history found no evidence of a dioxin relationship for the five respiratory illnesses studied. Physical examinations revealed significantly increased risk of thorax and lung abnormalities for Ranch Hand participants in the high current dioxin category relative to comparisons in the background category; however, the authors believed the findings to be related to the association between dioxin and body fat noted in the general health assessment, because obesity is known to cause a reduction in vital capacity (76).

A study of chemical plant workers with mean serum dioxin levels (lipid adjusted) of 200 ppt, found no difference between workers and referents in the risk for chronic bronchitis or chronic obstructive pulmonary disease (COPD). Analysis of the ventilatory function data revealed no association between history of exposure and the forced expiratory volume at one second (FEV1), forced vital capacity (FVC), or to the ratio of FEV1 to FVC (FEV1/FVC%) (77).

Few animals studies were located in the literature that addressed respiratory findings associated with dioxin exposure. Those that were located reported hyperplastic lesions in the terminal bronchioles and adjacent alveoli of rats, but not mice (78) and hemorrhage, hyperplasia, and metaplasia of bronchial epithelium in monkeys (79). On the other hand, rats exposed chronically and mice exposed intermittently to dioxin by gavage (80) and rats and mice exposed chronically by means of their diet (81) showed no adverse respiratory effects.

Anemia and Other Blood Disorders

Reporting for anemia and other blood disorders "in the last 12 months" was statistically significantly increased for all registrants (specifically the 55 through 64 years of age group) and the male subgroup at Baseline. The increases were statistically significant for only these subgroups at Followup 1, and there were no statistically significant increases at Followup 2. The small number reported was a factor in determining statistical significance. It should be noted that the wording for this question on the Dioxin Subregistry questionnaire closely matched that on the NHIS questionnaire.

Reports in the literature of anemia or other blood disorders relative to dioxin exposure have varied. In the Missouri pilot health study, routine hematology tests showed no consistent differences, with the exception that the mean platelet count was elevated in the high risk group (82); however, all platelet counts were within normal ranges (9). In the Quail Run population, however, there were statistically significant differences in the mean white blood cell count, mean absolute granulocyte count, and mean percentage of monocytes in the white blood cell differential count. When the exposure groups were compared for prevalence of test results outside the normal range, the exposed group was found to have a statistically significantly increased prevalence of elevated white blood cell count (10). Prolonged prothrombin time in adults has also been reported following dioxin exposure (83).

The general health assessment of the Ranch Hand population found that the erythrocyte sedimentation rate was statistically significantly related to both the initial and current serum levels of dioxin. The hematologic results, however, revealed no evidence that overt hematopoietic toxicity was related to dioxin exposure. Erythrocyte sedimentation rate, white blood cell count, platelet count, and IgA were positively associated with dioxin. The authors believed these findings suggested the presence of a chronic dose-related inflammatory response (76). It should be noted that an increase in natural killer cells was also reported for workers 17 years after their exposures (84).

In 1989, the hypothesis was formulated that dioxins could cause a vitamin K deficiency state in the newborn (85), potentially resulting in late hemorrhagic disease in the newborn, such as is caused by phenobarbital. Dioxins are transported over the human placenta and are found in breast milk in relatively high concentrations (47). In addition, it is known that dioxins are strong inducers of D-T diaphorase and that this enzyme can convert vitamin K (86). In a few mothers, dioxin concentrations capable of inducing D-T diaphorase were found in their milkfat; thus, it was possible that enzymes were induced in their infants' liver cells if the same concentration was present in the livers of the infants by transplacental transport or by ingesting breast milk or both. The mechanism for this action is unknown; however, the fact that the late form of hemorrhagic disease of the newborn has been described in England, Holland, and West Germany is interesting in light of the WHO reports that the dioxin content in breast milk is higher in these areas than elsewhere (87). In addition, animal studies provide support for the hypothesis of vitamin K deficiency (88). Subsequent human studies (87) have shown a reduced number of platelets with cumulative dioxin intake in newborns.

The organs that uniformly show lesions in animals exposed to dioxin are the thymus and other blood-forming organs (37). The thymus of dioxin-exposed animals shows marked reduction in size-often weighing 25% or less of normal in lethally intoxicated animals (89). There is loss of cortical lymphocytes that might progress to the point where only a thin zone of cortex remains. The medulla often contains necrotic cellular debris, which might be related to a depression of lymphocyte maturation factor, which is produced in the medulla (90). There is also a less pronounced depletion of lymphocytes in the thymic-dependent, periarterial lymphoid sheaths of the splenic lymphoid follicles. In animals, dioxin may cause thymic and peripheral lymph node atrophy (89,91-99).

In severely intoxicated animals, the bone marrow is usually hypocellular, which appears morphologically to be pancytopathic, but definitive studies have not been conducted to establish this. In chronically exposed animals, anemia, lymphopenia, and thrombocytopenia have been reported (100) as features of the disease, which further suggests that several elements of the bone marrow are affected. Anemia has been reported for both rhesus monkeys and rats (89,101,102).

In a study of rats, Weisberg and Zinkl (103) reported reduced platelets and nonsignificant changes in red and white blood cells. Zinkl et al. (104) further found these changes to be reversible in mice. The final effect of dioxin myelotoxicity has been postulated to be an alteration of stem cell maturation (105), at least for mice.

In conclusion, the literature concerning dioxin exposure and subsequent anemia or other blood disorders is varied. When viewed in conjunction with the literature, however, the results of the Dioxin Subregistry data analyses should be explored further. Medical confirmations of these reports are needed.

Skin Rashes, Eczema, and Other Skin Allergies

Skin rashes were reported in statistically significant excess in the Dioxin Subregistry population overall at Baseline, Followup 1, and Followup 2, and additionally for the subgroup aged 35 through 44 years at Followup 2. In addition to differences between the Dioxin Subregistry and NHIS, this finding might also reflect differences in the wording of this question between the respective questionnaires. The Dioxin Subregistry question was phrased more generally-skin rashes, eczema, or other skin allergies-than was the NHIS question, which was restricted to psoriasis, dermatitis, or dry (itching) skin.

The primary response to dioxin appears to be epithelial hyperplasia or altered differentiation, or both; chloracne and associated epidermal changes were the first lesions to be recognized as having these characteristics (49). Chloracne is the best known consequence of exposure to dioxin (106-118) and can persist for many years (60,119-121). Often a delay of 2 to 4 weeks occurs between exposure to dioxin and onset of signs or symptoms of chloracne. The disease will then progress and regress without additional exposure over a 4- to 6-month period. According to Suskind and Hertzberg (60), severe exposures (such as occurred in Nitro in 1949) can result in the development of chloracne that persists for 30 or more years. The Nitro workers also developed actinic elastosis in the area of chloracne; however, there was no evidence of tumor formation in the skin affected. Smokers in the exposed population had a higher incidence of chloracne.

Porphyria cutanea tarda (PCT), a disturbance of liver metabolism in which excess porphyrins are produced and excreted, has also been reported in individuals exposed to dioxin (107,117,122-126); however, it is considered by some to be relatively rare in humans (127). Some symptoms of PCT are exhibited as dermal effects, including hyperpigmentation, blistering, and an abnormal growth of hair on the face and body known as hirsutism. The NASIOM (59) has concluded that there is sufficient evidence to conclude an association exists between dioxin exposure and this outcome.

Nonspecific dermatitis has also been reported in response to dioxin exposure. Fitzgerald et al. (128) reported that some workers who were exposed to dioxin, as well as polychlorinated biphenyls and polychlorinated dibenzofurans, via a transformer fire and who complained of itching skin had a statistically significantly higher age-adjusted mean exposure index score than those without that symptom.

Caputo et al. (129) reported the occurrence of pruritic, nodulopustular lesions on the trunk and arms of some children about 15 days after dioxin exposure in the Seveso, Italy, accident. All the early lesions disappeared within one month following the accident, leaving no sequelae except from mild hyperpigmentation, possibly resulting from exposure to the sun. According to Homberger et al. (114) within the first 2 months following the accident, 1,600 individuals of all ages had been studied; of these, 447 had nonspecific dermatitis.

Hoffman et al. (10) in the Quail Run study found an increased incidence of nonspecific dermatitis; however, no chloracne or PCT was reported. Skin disorders were frequently (about 45%) reported in Vietnam veterans (130); however, the authors associated this with field activities and living conditions rather than dioxin exposure. For Ranch Hand participants with a later tour of duty in Vietnam (time since tour ended £18.6 years), there were statistically significant or marginally significant positive associations between current levels of dioxin and post-Southeast Asia acne and several of the acne-related physical examination variables (76). Chloracne has been linked to dioxin exposure in many studies; there is sufficient evidence to conclude a positive association (59).

Animals also show dermal responses to dioxin exposure. In Missouri, horses that had been exposed to dioxin-contaminated soil had skin lesions, alopecia, and edema (58). Hyperkeratosis, acanthosis, and necrosis were apparent upon examination of skin sections from these animals. The skin of nonhuman primates (79,89), rabbits (131), cattle, and certain hairless strains of mice (132,133) showed a characteristic form of follicular dermatitis, but this dermatitis was not observed in other strains of mice, rats, guinea pigs, or hamsters (100). Progressive weight loss, the first clinical sign of toxicity in the monkey, can be accompanied by alopecia, facial edema, and a dry scaly dermatitis over the rest of the body (37).

In general, the finding of excess skin problems in the Dioxin Subregistry were in keeping with the literature. Since specific skin conditions were not ascertained by the Subregistry, it would be valuable for researchers to further investigate the cases of skin conditions to identify specific skin problems.

Stroke

Stroke was reported in statistical excess at Baseline for the overall population, registrants 45 through 54 years of age, and females 45 through 54 years of age. There was no reported excess at Followup 1; however, at Followup 2 a statistically significant excess was reported for the overall population and those aged 45 through 54 years. The wording of the NHIS and Dioxin Subregistry health questions for this outcome was a close match. The time frame was ever had.

Very few studies were found in the literature investigating a potential relationship between dioxin exposure and stroke. One study, using chloracne as a measure of dioxin exposure, found strokes to be more frequent than expected (RR = 3.8) when subjects were compared with individuals without chloracne. In a mortality study of Vietnam veterans in Massachusetts, Kogan and Clapp (134) found there was a significantly higher risk (PMR = 1.6, adjusted for age) for stroke in Vietnam veterans when compared with non-Vietnam veterans; however, the confounders were not identified.

In Seveso, the mortality due to cerebrovascular diseases overall was as expected, with the notable exception of males in the area closest to the plant (67,68). Males in the zone closest to the facility (Zone A) had a relative risk of 3.30 (1.4-8.0) for mortality due to cerebrovascular disease. The authors noted, however, that interpretation was hampered by the short observation period, small number of deaths from certain causes, and poor exposure definition (67). In a study of chemical plant workers, mortality due to vascular lesions of the central nervous system was statistically nonsignificantly elevated (135). In a study of mortality and incidence of cancer at four phenoxy acid herbicide plants, Coggon et al. (64) found increased mortality from circulatory disease in only one cohort; however, they could discern no occupational cause for this excess with a nested case-control study. Hypertension, which has been associated with stroke, has been reported in some studies (71,76) while others did not find this association (9,60).

In a study of U.S. workers exposed to dioxin, Fingerhut et al. (136) found statistically significant reductions in the mortality rates for diseases of the circulatory system, primarily because of fewer deaths from stroke; however, the authors noted that the low mortality from circulatory disease could be a reflection of the "healthy worker" effect. Other worker studies have also reported negative findings (66,135,137).

Although not specifically addressed by the Dioxin Subregistry questionnaire, lipid abnormalities might confer increased risk of vascular disease. In a laboratory study of British workers 10 years after exposure, Martin (138) found increased levels of cholesterol and triglycerides. Increases in cholesterol were also observed in Czechoslovakian workers examined 10 years after exposure (139). Acute medical consequences following exposure to dioxin-contaminated substances in industrial accidents included abnormalities in lipid levels (136). In the Nitro population, total plasma lipids and prothrombin times were abnormal (60). In the Ranch Hand study of Vietnam veterans, cholesterol, high-density lipoprotein (HDL), and cholesterol-HDL ratio were associated significantly with dioxin (76). Elevations of levels of blood cholesterol (106,107,122) and triglycerides (119) have also been reported in other studies. NASIOM (59) has also classified lipid disorders in group 2.

In contrast, Moses et al. (140) followed a cohort of workers in which no association between dioxin exposure and serum cholesterol or triglycerides was found. Mocarelli et al. (120) followed 400 Seveso children and found no increases in the level of serum cholesterol. In the Quail Run study, Hoffman et al. (10) found lowered cholesterol and serum triglycerides in the exposed group.

Excess reports of stroke in the Dioxin Subregistry population should be explored further; however, it should be noted that a larger proportion of dioxin registrants smoke than do individuals nationwide. Smoking has been associated with stroke; therefore, these results should be interpreted with caution. Given the limited amount of information available on dioxin exposure and stroke, this potential association needs further investigation.

Urinary Tract Disorders, Including Prostate Trouble

A statistically significant excess of urinary tract disorders was reported by the total population and the female subpopulation at Baseline and Followups 1 and 2. Statistically significant increases were found for several age, sex, and age-sex subgroups, but the numbers were small making interpretation problematic. The wording for this health condition in NHIS was not an exact match with the wording in the Dioxin Subregistry. The NHIS question was specific for bladder disorders, while the Dioxin questionnaire included the broader category of all urinary tract disorders, as well as prostate trouble, which might have accounted for a portion of the excess reporting in the Dioxin Subregistry.

Few reports in the literature specifically address urinary tract disorders in humans following dioxin exposure. One child exposed to dioxin in Missouri had hemorrhagic cystitis and pyelonephritis (58,141). Following other individuals in Missouri considered to be in the high exposure risk cohort, Webb (82) found what appeared to be a trend of increased urinary tract problems, as reported from the medical history section of the Missouri pilot health survey questionnaire. The urinalysis showed a statistically nonsignificant increase in urinary white blood cells and in red blood cells, and a positive dipstick from blood. There was also a suggestion of microscopic hematuria in the high-risk group (9). Urinalysis on this group did not indicate any kidney effects (9,10). In the Air Force health study, under the maximal assumption (but not the minimal), the initial dioxin analyses found statistically significantly increased risk of urinary occult blood cells, but results were not statistically significant for the other models (76). The Air Force Health Study (142) also reported an increased risk for birth defects of the urinary system in offspring of Operation Ranch Hand participants; however, no underlying association was concluded for this outcome and dioxin exposure.

The epithelium of the urinary tract has been shown to respond to dioxin via hyperplasia or altered differentiation, or both (49). In addition, a teratogenic effect of dioxin has been reported to be hydronephrosis (distension of the kidneys) due to hyperplasia of the epithelium of the ureter (143-147). Dioxin can cause squamous metaplasia of epithelium at different sites, including the urinary bladder (131). The urothelium of the renal pelvis, ureter, and urinary bladder of guinea pigs, cattle, and monkeys exposed to dioxin show varying degrees of hyperplasia; in contrast, mice and rats do not show this lesion (148,149). An increase in the incidence of cystic kidneys has also been reported for rats exposed to dioxin (150). Other effects reported have included a slight dilation and impairment of Bowman's capsules and convoluted tubules in rats, following ad libitum feeding (151,152). Finally, kidney anomalies (mainly hydronephrosis) have been reported in the offspring of dams acutely exposed to dioxin during gestation (93,143,150,151,153,154).

It is important to note that some of the conditions reported here may be due to compromised immune systems (for example, excesses reported for urinary tract disorders may be infections). Dioxin is a known immunosuppressant (155). Signs of immunosuppression have been observed in exposed adults (76,156) and children exposed in utero (157); however, other studies have reported negative results (120,158,159). Dioxin also suppresses resistance to infections in animals through decreased humoral immunity (160-163), and suppresses cellular immunity (96,164,165). As mentioned previously, thymic atrophy is frequently seen in animals following dioxin exposure.

Given the results, the possible association between dioxin exposure and urinary tract disorders should be explored further.

Cancer

The Dioxin Subregistry question asked for information on all cancers registrants had ever had; the NHIS asked for cancers treated in the last 12 months. Of the 17 registrants reporting positively to having ever been told they had cancer or treated by a health care provider for cancer, 8 persons reported currently receiving treatment or date of first treatment was within the past 12 months. Statistically significant excesses of reporting for the 12-month time frame for all cancers were reported by the Dioxin Subregistry population at Baseline (8 observed versus 2.5 expected) and the 9-month time frame for Followup 2 (7 observed versus 1.7 expected). For Followup 1 (a 15-month time frame), 5 were observed, 3 expected. Analyses of specific cancers were not carried out because of the small numbers, the number of different types of cancer reported, and the variations in reporting patterns-three registrants reported positively at all three data collection periods, one at two periods, and the others once. It should be noted that the date of first treatment was reported to have been after the exposure (after 1972) for all but one of the cancers.

As reported in EPA's health assessment document (166), although the animal evidence for carcinogenicity of dioxin is sufficient the human evidence is regarded as inadequate using the EPA classification criteria because of the difficulty of attributing the observed effects solely to the presence of dioxin that occurs as an impurity in the phenoxyacetic acids and chlorophenols. Both the EPA and National Institute for Occupational Safety and Health (NIOSH), as well as others (167-169), consider dioxin to be a cancer promoter in conjunction with certain other chemicals. NIOSH classifies dioxin as a "potential occupational carcinogen," while EPA considers dioxin to be a "probable human carcinogen" (170).

Given that the Dioxin Subregistry has a small population, the likelihood of seeing rare cancers is unlikely. In addition, the latency period for many of the cancers reported in the studies reviewed in the following pages is much longer than the follow-up period for the Dioxin Subregistry population. It should also be noted that most of the studies reviewed are occupational studies; therefore their relevancy to low-dose environmental exposures might be small. In addition, many epidemiological studies have the limitations of reduced power, inadequate exposure assessment, and relatively short latency periods; however, these studies are presented in order to update the information available at the beginning of the Dioxin Subregistry Baseline data collection effort.

Numerous epidemiologic studies investigating the possible relationship between dioxin exposure and cancer have been conducted (Table 6-2). Some were concerned with manufacturers of products known to be contaminated with dioxin (115,116,171-173); others with exposure to phenoxy acid herbicides, some of which might contain dioxin as an impurity (65,174-185). Fingerhut et al. (136,186) found an increase in mortality from all cancers (SMR = 1.46) in male dioxin-exposed workers with more than 1 year exposure and a minimum latency period of 20 years. The finding for all cancers is consistent with the Zoeber study of German workers, in which a similar finding of excess total cancers was reported in a subgroup with chloracne who had been exposed 20 or more years earlier (194). In a study of Vietnam veterans, those with higher exposure scores had higher estimated risks for fathering babies with "other neoplasms" (196).

Other studies have reported negative findings. May (119,197) followed workers exposed to dioxin in an explosion in a Coalite TCP plant in England. None of these or other potentially exposed persons studied developed malignant disease. Ott et al. (171) followed Dow workers and found no excess cancer risk. Bond et al. (135) followed workers with chloracne and found no consistent pattern of mortality. Zack and Suskind (172) followed Monsanto's Nitro workers and found no increase in overall cancer mortality. The Australian Vietnam veterans study (198,199) also failed to disclose any excess cancer risk associated with exposure to herbicides potentially contaminated with dioxin. In Seveso, cancer mortality as a whole was below expectations (67,68). Finally, the Missouri pilot health study did not find a statistically significant difference in the numbers of cancers reported (82).Various specific cancers have also been investigated with respect to a potential relationship with dioxin exposure, such as cancers of the buccal cavity and pharynx (see Table 6-3). There is limited/suggestive evidence of no association between exposure to dioxin and gastrointestinal cancers (review in 59) (see Table 6-4).

Reports in the literature of associations between dioxin exposure and liver cancer were mostly negative (10,67,68,136,172,200) (Table 6-4). The only positive finding of an association was for a case-control study of liver cancer in Vietnam. For those who lived in an area in which phenoxy

Table 6-2.—All cancers (International Classification of Diseases-9 codes 140-208) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Axelson and Sundell (187)	Swedish rail workers with >40 days of spraying	207	1957-72	2,4-D 2,4,5-T	no excess
Riihimaki et al (178)	Male Finnish herbicide sprayers	1,926	1972-80	2,4-D 2,4,5-T	no excess
Wiklund and Holm (184)	Swedish male agricultural and forestry workers	354,620	1961-79	PH	no excess
Cook et al (116)	USA workers (Dow) with chloracne	61	1964-78	TCP	SMR = 1.88
Fett et al (188)	Australia Vietnam veterans	19,205	1984	PH	no excess
Ott et al (171)	USA workers (Dow)	204	1950-76	2,4,5-T	SMR = 0.28
Bond et al (135)	USA workers	878	1945-82	2,4-D	no excess
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.83 RR = 0.96 RR = 0.90 RR = 0.85 RR = 0.83 RR = 0.84
Fingerhut et al (186)	USA workers ³20 years latency,<1 year exposure ³20 years latency,³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.15 SMR = 1.02 SMR = 1.46
Manz et al (190)	German production workers male female	1,184 399	1952-87	TCDD	SMR = 1.24 SMR = 0.94
Zack and Suskind (172)	USA workers (Nitro, WV) with chloracne	121	1949-78	2,4,5-T	SMR = 1.00
Zack and Gaffey (191)	USA workers (Nitro, WV)	884	1955-77	2,4,5-T	PMR = 0.82
Fingerhut et al (192)	USA workers	452 2,092	1987	TCDD	SMR = 1.18 SMR = 1.02
Bertazzi et al (193)	Seveso, Italy residents Zone A females males Zone B females males Zone R females males	724 total 4,824 total 31,647 total	1977-1986	TCDD	RR = 1.0 RR = 0.7 RR = 0.8 RR = 1.1 RR = 0.9 RR = 0.9

Table 6-2.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Bertazzi et al (68)	Seveso, Italy residents Zone A females   males   Zone B females   males   Zone R females   males	724 total         4,699 total       31,800 total	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.62 RR = 0.53 RR = 0.87 - RR = 0.90 RR = 0.84 - RR = 0.67 RR = 0.87 RR = 0.94 RR = 1.48 RR = 0.89 RR = 0.80 RR = 0.60 RR = 0.87 RR = 0.46 RR = 1.19 RR = 0.86
Bond et al (189)	USA workers (Dow) with chloracne	323	1964-83	TCDD	SMR = 0.66
Zoeber et al (194)	German workers (BASF) with chloracne with 20+ years latency	247	1953-87	TCDD	SMR = 1.17 SMR = 1.39 SMR = 2.01
Kogevinas et al (195)	International register of workers, females	701		PH, CP TCDD	SIR = 0.96 SIR = 2.22

N-Number in population

PH-Phenoxy herbicides

2,4-D-2,4-Dichlorophenoxy acetic acid

2,4,5-T-2,4,5-Trichlorophenoxy acetic acid

TCP-Trichlorophenol

SMR-Standardized mortality ratio

-No value reported

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

PMR-Proportional mortality ratio

SIR-Standardized incidence ratio

CP-Chlorophenols

herbicide had been sprayed, the relative risk was found to be 5.2 for liver cancer; however, other confounders were difficult to ascertain (203).

Table 6-3.—Buccal cavity and pharynx cancers (International Classification of Diseases-9 codes 140- 149) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Buccal cavity and pharynx (ICD-9 codes 140-149)
Bertazzi et al (67)	Seveso, Italy male residents		1976-1981 1982-1986 1976-1986	TCDD	RR = 1.20 RR = 1.14 RR = 1.18
Bertazzi et al (68)	Seveso, Italy male residents Zone B   Zone R		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 2.49 RR = 1.33 RR = 2.04 RR = 1.05 RR = 1.14 RR = 1.08
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 0.70 SMR = 1.45 SMR = 0.90
Bertazzi et al (193)	Seveso, Italy male residents Zone B Zone R		1977-1986	TCDD	RR = 1.7 RR = 1.2
Other parts (ICD-9 codes 142-145)
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.05 SMR = 0.00 SMR = 3.29
Pharynx (ICD-9 codes 146-149)
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 0.88 SMR = 2.98 SMR = 0.00

N-Number in population

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

In Seveso, cancers of the gall bladder exhibited a slightly, but not statistically significantly, elevated relative risk (67,68); however, Fingerhut et al. (136,186) reported statistically nonsignificantly lower SMRs for cancer of the gallbladder for workers in a high exposure subcohort.

The reports of cancer of the biliary tract are varied. In Seveso, Bertazzi et al. (68) reported that mortality due to cancers of the biliary tract was slightly, but not statistically significantly, elevated; the incidence of hepatobiliary cancer was also elevated. For dioxin-exposed workers,

Table 6-4.—Digestive system cancers (International Classification of Diseases-9 codes 150-159) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Digestive system (ICD-9 codes 150-159)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.84 RR = 0.82 RR = 0.83 RR = 0.92 RR = 0.86 RR = 0.89
Bertazzi et al (68)	Seveso, Italy Zone B females		1976-1981 1982-1986 1976-1986	TCDD	RR = 0.51 RR = 0.79 RR = 0.65
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.12 SMR = 1.11 SMR = 1.40
Bertazzi et al (193)	Seveso, Italy residents Zone A females males Zone B females males Zone R females males	724 total 4,824 total 31,647 total	1977-1986	TCDD	RR = 1.7 RR = 0.7 RR = 1.1 RR = 0.9 RR = 0.9 RR = 0.9
Esophagus (ICD-9 code 150)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.36 RR = 0.51 RR = 0.97 RR = 4.29 - RR = 1.09
Bertazzi et al (68)	Seveso, Italy residents Zone R females   males	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.57 RR = 0.59 RR = 1.12 RR = 4.85 - RR = 1.24
Manz et al (190)	German male production workers	1184	1952-87	PH	SMR = 1.86

Table 6-4.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³ year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.52 SMR = 1.65 SMR = 2.00
Stomach (ICD-9 code 151)
Axelson et al (176)	Swedish railway workers	348	1957-74	PH	SMR = 7.7
Thiess et al (201)	German workers (BASF)	74	1953-80	TCDD	SMR = 4.3
Ott et al (199)	USA manufacturing workers	2,187	1940-82	TCP	O/E = 6/3.8
Bertazzi et al (68)	Seveso, Italy residents Zone B males   Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.05 RR = 1.42 RR = 1.23 RR = 0.77 RR = 0.83 RR = 0.80 RR = 1.06 RR = 1.04 RR = 1.05
Berrtazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.79 RR = 0.88 RR = 0.84 RR = 0.93 RR = 1.01 RR = 0.97
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.03 SMR = 1.04 SMR = 1.38
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males		1977-1986	TCDD	RR = 0.6 RR = 1.0 RR = 1.0 RR = 0.9
Manz et al (190)	German production workers	1,148	1952-84	PH	SMR = 1.21
Lynge (181)	Danish production workers	4,459	1982	PH, CP	RR = 1.3
Colon and small intestine (ICD-9 codes 152-153)
Lynge (181)	Danish production workers	4,459	1982	PH, CP	SMR = 4.71

Table 6-4.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Hardell (202)	Northern Sweden residents	154	1974-78	PH CP	RR = 1.3 RR = 1.8
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.90 RR = 1.03 RR = 0.96 RR = 0.43 RR = 0.97 RR = 0.68
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.22 SMR = 1.17 SMR = 1.78
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males		1977-1986	TCDD	RR = 0.6 RR = 0.5 RR = 0.8 RR = 1.1
Manz et al (190)	German male production workers	1,148	1952-87	TCDD	SMR = 0.92
Ott et al (199)	USA manufacturing workers	2,187	1940-82	2,4,5-T	SMR = 1.41
Rectum (ICD-9 code 154)
Lynge (181)	Danish production workers	4,459	1982	PH	SMR = 4.08
Bertazzi et al (68)	Seveso, Italy residents Zone B males   Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.82 RR = 1.56 RR = 1.70 RR = 1.01 RR = 0.88 RR = 0.95 RR = 1.09 RR = 1.34 RR = 1.16
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.09 RR = 0.95 RR = 1.02 RR = 1.19 RR = 1.17 RR = 1.18

Table 6-4.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 0.89 SMR = 1.00 SMR = 1.15
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males		1977-1986	TCDD	RR = 1.3 RR = 1.4 RR = 0.6 RR = 1.1
Hepatobiliary (ICD-9 codes 155,156)
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males		1977-1986	TCDD	RR = 3.3 RR = 1.8 RR = 0.9 RR = 0.5
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.16 SMR = 1.00 SMR = 0.59
Hardell et al (200)	Male residents of northern Sweden	102 cases	1974-81	PH	OR = 1.7
Liver cancers (ICD-9 code 155)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.25 RR = 0.63 RR = 0.48 RR = 0.58 RR = 0.32 RR = 0.38
Bertazzi et al (68)	Seveso, Italy residents Zone B males   Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	- RR = 1.96 RR = 12.07 RR = 0.29 RR = 0.46 RR = 0.40 RR = 0.66 RR = 0.37 RR = 0.43

Table 6-4.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Bertazzi et al (193)	Seveso, Italy residents Zone B males Zone R females males		1977-1986	TCDD	RR = 2.1 RR = 0.5 RR = 0.2
Gall bladder and biliary tract (ICD-9 code 156)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.12 RR = 1.82 RR = 1.47 RR = 1.88 RR = 1.37 RR = 1.66
Bertazzi et al (68)	Seveso, Italy residents Zone A females   Zone B females   Zone R females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 21.93 - RR = 12.07 RR = 3.50 RR = 4.23 RR = 3.86 RR = 1.29 RR = 1.04 RR = 1.18
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males		1977-1986	TCDD	RR = 4.9 RR = 2.3 RR = 1.0 RR = 1.0
Pancreas (ICD-9 code 157)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.64 RR = 0.54 RR = 0.60 RR = 1.28 RR = 0.54 RR = 0.96

Table 6-4.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Bertazzi et al (68)	Seveso, Italy residents Zone B males   Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.08 RR = 1.12 RR = 1.11 RR = 0.60 RR = 0.47 RR = 0.54 RR = 1.47 RR = 0.61 RR = 1.09
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 0.84 SMR = 0.41 SMR = 1.00
Peritoneum and retroperitoneum (ICD-9 code 158)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 8.28 - RR = 3.26 RR = 1.15 RR = 5.98 RR = 1.95
Bertazzi et al (68)	Seveso, Italy residents Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 9.63 - RR = 3.79 RR = 1.32 RR = 6.76 RR = 2.24
Unspecified (ICD-9 code 159)
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.84 - -

N-Number in population

PH-Phenoxy herbicides

2,4,5-T-2,4,5-Trichlorophenoxy acetic acid

TCP-Trichlorophenol

-No value reported

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

CP-Chlorophenols

however, Fingerhut et al. (136,186) reported that the SMRs were statistically nonsignificantly lower for cancer of the biliary passages in the high exposure subcohort.

Exposure to phenoxy herbicides and chlorophenols potentially contaminated with dioxin has been shown in some studies (115,176) to be associated with stomach cancer, but no outcome has been conclusively established or rejected (136,186). In two cohort studies of U.S. chemical workers, statistically nonsignificant excesses in mortality were observed for cancers of the stomach (172,199). In Seveso, Bertazzi et al. (67,68) noted suggestions of increased risk for deaths from peritoneal cancer. Assessment of results from other dioxin populations, however, does not show elevated stomach cancer rates (173,191) or elevated rates could not be attributed to dioxin exposure (135).

With respect to the rest of the gastrointestinal tract, two esophageal cancer deaths made up a large numerical increase in the relative risk in Seveso (136,186). In two cohort studies of U.S. chemical workers, statistically nonsignificant excesses in mortality were observed for cancers of the intestine (172,199). Male Danish workers exposed to phenoxy herbicides had an elevated, but statistically nonsignificant, excess of rectal cancer (181). A statistically significant association was also observed for colon cancers.

NASIOM (59) has indicated there is suggestive, but inconsistent, evidence that exposure to Agent Orange might be associated with trachea, larynx, and lung cancers. Among U.S. chemical workers, statistically nonsignificant excesses in mortality were observed for cancers of the lung (172,199) (Table 6-5). In a subcohort of workers with 20 years or more latency, mortality from respiratory cancer was statistically significantly increased in the high dioxin exposure subcohort, but not in the cohort with less than 1 year of exposure. This difference was probably not due to confounding by smoking; however, asbestos might have contributed to mortality from lung cancers in the cohort, since two deaths were due to mesotheliomas (136,186). This study did not, however, find excess nasal cancer. Lynge (181), in a report on a cohort of Danish herbicide workers, noted an association (SMR = 2.06) for lung cancer in individuals with a minimum exposure of 2 weeks and no latency period. In Seveso adults, a substantial constancy of the rate ratios for the leading cancer causes (lung in men) was apparent. As to other cancer causes, statistically significantly increased relative risks were noted for pleura in the first study period (67,68).

The NASIOM has concluded there is insufficient/inadequate evidence to propose an association between nasal/nasopharyngeal cancer (59); however, there is limited/suggestive evidence of an association with respiratory cancers (lung, larynx, trachea) (see Table 6-5).

Recently, NASIOM (59) indicated there was sufficient evidence to suggest a positive correlation between exposure to Agent Orange and soft-tissue sarcomas (STS). Military service in Vietnam during the period in which Agent Orange, a herbicide contaminated with dioxin, was used has been investigated for an association with development of STS. The Department of Veterans Affairs (DVA) currently offers compensation for STS, even though links have never been proven (42). Greenwald et al. (207) reported no statistically significant association between STS among Vietnam-era veteran-age males and military service in Vietnam; however, the study was criticized for the use of proxies for exposure, as well as for the short latency period (Table 6-6). A followup of that study also reported no excess of STS (208). A mortality study of Australian Vietnam-era veterans reported no statistically significant difference in the death rates from STS (209). In 1985, Kogan and Clapp (134) reported their examination of STS mortality, based on vital statistics data, among Vietnam-era (1958-1973) veterans residing in Massachusetts. They found that the relative

Table 6-5.—Respiratory system cancers (International Classification of Diseases-9 codes 160-165) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Respiratory system (ICD-9 codes 160-165)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.71 RR = 1.09 RR = 0.89 RR = 0.85 RR = 0.61 RR = 0.73
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.13 SMR = 1.03 SMR = 1.42
Bertazzi et al (193)	Seveso, Italy residents Zone B males Zone R females males		1977-1986	TCDD	RR = 1.1 RR = 1.4 RR = 0.9
Nose and nasal (ICD-9 code 160)
Hardell et al (204)	Residents of northern Sweden	71 cases	1970-79	PH, CP	RR = 2.1 RR = 6.7
Bertazzi et al (193)	Seveso, Italy Zone R females		1977-1986	TCDD	RR = 2.6
Larynx (ICD-9 code 161)
Bertazzi et al (67)	Seveso, Italy males	30,703 total	1976-1981 1982-1986 1976-1986	TCDD	RR = 0.55 RR = 1.10 RR = 0.84
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 2.11 SMR = 2.97 SMR = 2.68
Lung, trachea, and bronchus (ICD-9 code 162)
Barthel (205)	Agricultural workers	1,658	1948-72	PH	SMR = 2.0
Lynge (181)	Danish production workers	4,459	1982	PH	SMR = 2.06
Zack and Suskind (172)	USA workers (Nitro, WV)	121	1949-78	TCP	SMR = 1.75

Table 6-5.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.70 RR = 1.05 RR = 0.87 RR = 0.67 RR = 0.73 RR = 0.70
Bertazzi et al (68)	Seveso, Italy residents Zone A males   Zone B males   Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	- RR = 2.02 RR = 0.95 RR = 1.11 RR = 1.83 RR = 1.45 RR = 0.66 RR = 0.92 RR = 0.78 RR = 0.76 RR = 0.84 RR = 0.80
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.11 SMR = 0.96 SMR = 1.39
Zack and Gaffey (191)	USA production workers (Nitro, WV)	58	1955-77	2,4,5-T	PMR = 1.59
Fingerhut et al (192)	USA workers	452	1987	TCDD	SMR = 1.44
Saracci et al. (206)	IARC cohort probably exposed	173 cases 11 cases		TCDD	RR = 1.0 RR = 2.2
Bertazzi et al (193)	Seveso, Italy residents Zone A males Zone B males Zone R females males		1977-1986	TCDD	RR = 0.8 RR = 1.1 RR = 1.5 RR = 0.8
Fingerhut et al (192)	USA workers	2,092	1987	TCDD	SMR = 0.78

Table 6-5.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Pleura (ICD-9 code 163)
Bertazzi et al (67)	Seveso, Italy male residents	30,703 total	1976-1981 1982-1986 1976-1986	TCDD	RR = 11.30 RR = 3.64 RR = 5.63

N-Number in population

PH-Phenoxy herbicides

2,4,5-T-2,4,5-Trichlorophenoxy acetic acid

TCP-Trichlorophenol

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

PMR-Proportional mortality ratio

CP-Chlorophenols

-No value reported

risk for STS among veterans compared with nonveterans in the state was 5.2. Kang et al. (210), reporting on the findings from a case-control study of STS and past Vietnam service based on military records (used to determine whether service was related to the sarcoma occurrence), found a statistically nonsignificant odds ratio of 0.83.

Case-control studies from Sweden (175,177,218) and Denmark (181) initially suggested a relationship between exposure to 2,4-D and 2,4,5-T (and presumably dioxin) and the development of STS. Studies of chemical workers have reported that statistically nonsignificant excesses in mortality were observed for the International Classification of Disease (ICD) categories describing STS (172,199). In addition, several cases of STS have been reported in the United States among workers involved in the manufacture or use of phenoxy acid herbicides (219-221); however, no clear evidence was found for a causal association between any cause of death and potential occupational exposures to the higher chlorinated phenols, derivative products, or chlorinated dioxins. Mortality from STS was statistically nonsignificantly elevated for dioxin-exposed U.S. workers overall; however, in the subcohort with at least 1 year of exposure and at least 20 years of latency, mortality was statistically significantly increased for STS (136,186).

In contrast, other studies have not found a relationship between phenoxyacetic acid exposure and STS (182,183,211,212). Vineis et al. (182) compared the herbicide exposure histories and STS cases and population controls in an area of northern Italy; the odds ratio for men was 0.9; for women, 2.7. Manz et al. (190), reporting on a retrospective cancer mortality study of chemical workers in a herbicide plant in Hamburg, found no deaths due to STS. No cases of STS were reported in either the residents of Quail Run Mobile Home Park (10) or the Missouri pilot study (82).

Followup of the Seveso population disclosed the relative risk of STS was 2.11 (not statistically significant) for the exposed (222). Puntoni et al. (223) noted, however, that the incidence of STS in the Seveso area was high even before the accident. Suggestive increases in mortality due to STS were noted by Bertazzi et al. (67,68); however, interpretation was hampered by the short observation

Table 6-6.—Connective and other soft tissue cancers (International Classification of Diseases-9 code 171) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Hardell and Sandstrom (175)	Male Swedish cases	52	1970-77	PH, CP	OR = 5.3
Eriksson et al (177)	Southern Swedish residents	110	1974-78	PH	OR = 6.8
Smith et al (211)	New Zealand chemical applicators	80	1976-80	PH	OR = 1.03
Greenwald et al (207)	NY State Vietnam veterans	281	1984	PH	OR = 0.70
Hoar et al (183)	Kansas workers	133	1976-82	2,4-D 2,4,5-T	OR = 1.4
Kang et al (210)	USA Vietnam veterans	234	1969-83	PH	OR = 0.83
Woods et al (212)	Male agriculture and forestry workers (WV) with chloracne	128	1983-85	PH, CP	OR = 0.80 OR = 3.3
Vineis et al (213)	Italian rice weeders males females	37 31	1981-83	PH	OR = 0.90 OR = 2.7
Lynge (181)	Danish production workers with 10 years latency	4,459	1982	PH	SMR = 2.7 SMR = 3.7
Smith et al (180)	New Zealand males railworkers meatworkers	112	1955-79	PH, CP	OR = 3.2 OR = 7.2
Kang et al (214)	USA Vietnam veterans Army combat Army Reg. III Marines	281	1975-80	PH	OR = 0.8 OR = 2.6 OR = 8.6 OR = 1.3
Milham (215)	USA farmers	429,926		PH	OR = 1.52
Balarajan and Acheson (179)	English and Welsh farmers and foresters	1,961	1968-76	PH	RR = 1.7
Wiklund and Holm (184)	Swedish male agricultural and forestry workers	354,620	1961-1979	PH	RR = 0.9
Wiklund et al (185)	Swedish pesticide applicators	20,245	1965-84	PH	SIR = 0.9
Kogan and Clapp (134)	Massachusetts Vietnam veterans	840	1972-1983	PH	RR = 5.2
Fingerhut et al (192)	USA workers	452 2,092	1987	TCDD	SMR = 15.16 SMR = 3.84

Table 6-6.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Zoeber et al (194)	German workers (BASF)	247	1954-87	TCDD	SMR = 2.01
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	- RR = 2.82 RR = 5.43 - RR = 2.98 RR = 1.98
Bertazzi et al (68)	Seveso, Italy residents Zone R males   Zone B females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = inf RR = 3.27 RR = 6.33 - RR = 23.94 RR = 16.99
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 3.38 - SMR = 9.22
Bertazzi et al (193)	Seveso, Italy residents Zone R females males		1977-1986	TCDD	RR = 1.6 RR = 2.8
Saracci et al (206)	International workers 10-19 years latency Sprayers with 10-19 years latency	18,910	1955-90	PH, CP	SMR = 1.96 SMR = 6.06 SMR = 8.82
Hardell and Eriksson (216)	Northern Sweden residents	55 cases	1978-83	PH	RR = 3.3
Greenwald et al (217)	Italian workers Chemical industry Highway construction	130			OR = 1.77 OR = 1.50

N-Number in population

PH-Phenoxy herbicides

2,4-D-2,4-Dichlorophenoxy acetic acid

2,4,5-T-2,4,5-Trichlorophenoxy acetic acid

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

CP-Chlorophenols

inf-infinity

-No value reported

period, small number of deaths from certain causes, and poor exposure definition. In a follow-up study of cancer incidence in this same population for the same time period, the incidence of STS was elevated (193).

Skin cancers were among those reported in the Dioxin Subregistry population. Other studies of dioxin exposure and skin cancer have reported varied results (Table 6-7). The malignancy assessment of the Ranch Hand study (130) determined that serum dioxin levels were not statistically significantly associated with the incidence of skin neoplasms, except for an increase of basal cell carcinoma; however, these results might have been due to a multiple-testing artifact. It should be noted that previous Air Force health study reports showed that the Ranch Hand group had a statistically significantly increased risk of basal cell carcinoma relative to the comparison group; however, the skin neoplasm findings in the report did not support a positive dose-response relationship (76). A reported history of skin cancer in the Nitro worker population was not found to be statistically significantly associated with exposure (60). In Seveso, suggestively increased relative risks were noted for melanoma (67,68). One study was located implicating materials (PCBs) which might contain dioxin as a contaminant with melanoma (224). There is limited/suggestive evidence of no association with dioxin exposure (59).

Hanson (42) reported an antiestrogen effect for dioxin, which could account for decreases in spontaneous breast and uterine tumors (Tables 6-8 and 6-9). The results of epidemiological studies of dioxin and breast cancer, however, have varied. Bertazzi et al. (67,68) found a statistically significant decreased risk of breast cancer deaths; 4 years later the incidence of both breast and endometrial cancers was statistically significantly lower for this population (193). Relative risks consistently lower than unity were also estimated for ovarian cancer in the adult Seveso population (67,68). In a retrospective cancer mortality study of chemical workers in a herbicide plant in Hamburg, Germany, however, Manz et al. (190) reported that carcinoma of the breast was raised at 2.15 for 9 deaths. An interesting aspect of the relationship between dioxin and the neoplastic process was the observation of a dose-related decrease in uterine tumors (207). A cohort of Danish workers exposed to phenoxy herbicides before 1982 had a statistically elevated excess (SMR = 5.9) in the incidence of cervical cancer (181). NASIOM (59) classifies female reproductive cancers in group 2, indicating there is insufficient or inadequate evidence to associate these cancers with dioxin exposure.

Cancers of the prostate have also been observed in dioxin-exposed worker populations (135,172,199). In Seveso, mortality due to prostate cancer exhibited a borderline statistically significantly increased relative risk (67,68). NASIOM has indicated that there is suggestive, but inconsistent, evidence of an association between dioxin exposure and prostate cancer (59); testicular cancer was classified in group 2, indicating there was inadequate or insufficient evidence to suggest an association between this outcome and dioxin exposure.

The NASIOM (1994) has concluded there is inadequate/insufficient evidence for an association for female reproductive cancers and renal or testicular cancer; limited/suggestive evidence for prostate cancers; and limited/suggestive evidence of no association for bladder cancer (59).

A suggestive increase in mortality was seen for brain cancer in the population, aged 20 through 74 years, ever having lived in the area contaminated by dioxin after the Seveso incident in 1976 (68) (Table 6-10). Interpretation was hampered, however, by the short observation period, small number of deaths from certain causes, and poor exposure definition. The NASIOM (59) has concluded there is limited/suggestive evidence of no association.

Table 6-7.—Skin cancers (International Classification of Diseases-9 codes 172, 173) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Skin (ICD-9 codes 172, 173)
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 0.82 - SMR = 1.55
Bertazzi et al (193)	Seveso, Italy residents Zone A females males Zone B females males Zone R females males		1977-1986	TCDD	RR = 3.9 RR = 2.4 RR = 1.3 RR = 0.7 RR = 1.0 RR = 1.0
Lathrop et al (130)	USA Vietnam Project Ranch Hand veterans	1,026	1984	PH	RR = 2.35
Melanomas (ICD-9 code 172)
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 11.33 RR = 1.40 RR = 3.33 - RR = 0.58 RR = 0.33
Bertazzi et al (193)	Seveso, Italy residents Zone R females males		1977-1986	TCDD	RR = 0.9 RR = 0.7
Bertazzi et al (68)	Seveso, Italy residents Zone B males   Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	- RR = 11.35 RR = 9.06 RR = 13.12 - RR = 2.58 - RR = 0.67 RR = 0.39
Manz et al (190)	German male production workers	1,184	1952-87	TCDD	SMR = 1.28

N-Number in population

PH-Phenoxy herbicides

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

-No value reported

Table 6-8.—Breast cancers (International Classification of Diseases-9 code 174) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Bertazzi et al (67)	Seveso,Italy residents		1976-1981 1982-1986 1976-1986	TCDD	RR = 0.60 RR = 0.72 RR = 0.67
Manz et al (190)	German production workers	1,184	1952-87	TCDD	SMR = 2.15
Lynge (181)	Danish production workers	1,069	1982	PH, CP	RR = 0.9
Bertazzi et al (193)	Seveso, Italy residents Zone A females Zone B females Zone R females males		1977-1986	TCDD	RR = 0.5 RR = 0.7 RR = 1.1 RR = 1.2

N-Number in population

PH-Phenoxy herbicides

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

CP-Chlorophenols

Increases in mortality due to hematopoietic neoplasms (particularly leukemia in males) in Seveso did not appear to result from chance; however, the authors felt interpretation was hampered by the short observation period, small number of deaths from certain causes, and poor exposure definition (67) (Table 6-11). A follow-up study of cancer incidence in the same area during the first decade following exposure indicated that women were at an increased risk for multiple myeloma and myeloid leukemia (193). In two cohort studies of U.S. chemical workers, statistically nonsignificant excesses in mortality were observed for hematopoietic cancers (172,199). In a retrospective cancer mortality study of chemical workers in a herbicide plant in Hamburg, Germany, Manz et al. (190) reported an increase in mortality from all hematopoietic cancers.

In two cohort studies of U.S. chemical workers, statistically nonsignificant excesses in mortality were observed for lymphatic cancers (172,199). Increases in lymphatic neoplasms (particularly lymphoreticulosarcoma in males) were also reported for Seveso adults (67,68,193); however, no cases of lymphoma were reported for Quail Run Mobile Home Park residents (10). Exposure to phenoxy acid herbicides and chlorophenols potentially contaminated with dioxin has been shown in some studies to be associated with lymphoma (183,218,226,228,232), but no outcome has been conclusively established or rejected (136). NASIOM (59) has indicated there was evidence to suggest an association between exposure to Agent Orange and multiple myeloma, but that there were inconsistencies in the research. NASIOM also found insufficient or inadequate evidence to determine whether an association exists for dioxin exposure and leukemia.

Table 6-9.—Genitourinary organs cancers (International Classification of Diseases-9 codes 179-189) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Genitourinary (ICD-9 codes 179-189)
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males		1977-1986	TCDD	RR = 0.5 RR = 1.3 RR = 0.8 RR = 1.0
Uterus (ICD-9 codes 179-182)
Bertazzi et al (67)	Seveso, Italy females residents		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 1.65 RR = 0.89 RR = 1.30 RR = 4.86 - RR = 3.03
Bertazzi et al (68)	Seveso, Italy Zone R females		1976-1981 1982-1986 1976-1986	TCDD	RR = 1.89 RR = 1.03 RR = 1.49
Bertazzi et al (193)	Seveso, Italy females Zone A Zone B Zone R		1977-1986	TCDD	RR = 2.6 RR = 0.4 RR = 0.6
Cervix (ICD-9 code 180)
Lynge (181)	Danish production workers	1,069	1982	PH, CP	SMR = 5.9 RR = 1.3
Bertazzi et al (193)	Seveso, Italy Zone R females		1977-1986	TCDD	RR = 0.6
Corpus uteri (ICD-9 code 182)
Bertazzi et al (67)	Seveso, Italy female residents		1976-1981 1982-1986 1976-1986	TCDD	RR = 4.86 - RR = 3.03
Bertazzi et al (68)	Seveso, Italy Zone R females		1976-1981 1982-1986 1976-1986	TCDD	RR = 5.52 - RR = 3.45

Table 6-9.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Ovary (ICD-9 code 183)>
Bertazzi et al (67)>	Seveso, Italy female residents>	>	> 1976-1981> 1982-1986> 1976-1986>	TCDD>	RR = 0.41> RR = 0.49> RR = 0.46>
Bertazzi et al (68)>	Seveso, Italy Zone R females>	>	> 1976-1981> 1982-1986> 1976-1986>	TCDD>	RR = 0.47> RR = 0.57> RR = 0.53>
Bertazzi et al (193)>	Seveso, Italy Zone R females>	>	> 1977-1986>	TCDD>	RR = 1.1>
Male genital organs (ICD-9 codes 185-187)>
Fingerhut et al (186)>	USA workers> ³20 years latency, <1 year exposure> ³20 years latency, ³1 year exposure>	5,172> 1,516> 1,520>	1942-1984>	TCDD>	SMR = 1.11> SMR = 0.63> SMR = 1.49>
Prostate (ICD-9 code 185)>
Ott et al (199)>	USA manufacturing workers>	2,187>	1940-82>	2,4,5-T>	SMR = 1.90>
Bertazzi et al (67)>	Seveso, Italy male residents>	30,703> total>	1976-1981> 1982-1986> 1976-1986>	TCDD>	RR = 1.93> RR = 1.26> RR = 1.61>
Bertazzi et al (68)>	Seveso, Italy male residents> Zone B>  > Zone R>	>	>  > 1976-1981> 1982-1986> 1976-1986> 1976-1981> 1982-1986> 1976-1986>	TCDD>	> RR = 2.76> RR = 1.52> RR = 2.18> RR = 1.85> RR = 1.24> RR = 1.57>
Fingerhut et al (186)>	USA workers> ³20 years latency, <1 year exposure> ³20 years latency, ³1 year exposure>	5,172> 1,516> 1,520>	1942-1984>	TCDD>	SMR = 1.22> SMR = 0.67> SMR = 1.52>
Bertazzi et al (193)>	Seveso, Italy Zone R males>	>	> 1977-1986>	TCDD>	RR = 0.9>

Table 6-9.—Continued.>

> Investigators	Population>	N>	Date(s)>	Exposure>	Results>
Testis (ICD-9 code 186)>
Bullman et al (225)>	Vietnam veterans> Navy> Ground troops> Combat troops> Troops in III Corps area> Troops near spray tracts (90 days/8km)> Troops near spray tracts (3 days/2km)>	97 cases>	1982-91>	>	>  > OR = 2.60> OR = 0.46> OR = 0.91> OR = 1.10> OR = 0.99> OR = 1.39>
Bertazzi et al (193)>	Seveso, Italy males> Zone B> Zone R>	>	> 1977-1986>	TCDD>	> RR = 1.0> RR = 1.4>
Urinary organs (ICD-9 codes 188-189)>
Bertazzi et al (67)>	Seveso, Italy female residents>	>	> 1976-1981> 1982-1986> 1976-1986>	TCDD>	RR = 0.83> RR = 1.22> RR = 0.98>
Fingerhut et al (186)>	USA workers> ³20 years latency, <1 year exposure> ³20 years latency, ³1 year exposure>	5,172> 1,516> 1,520>	1942-1984>	TCDD>	SMR = 1.48> SMR = 1.28> SMR = 1.49>
Bladder (ICD-9 code 188)>
Zack and Gaffey> (191)>	Production workers (Nitro, WV)>	884>	1955-77>	2,4,5-T>	SMR = 9.9>
Bertazzi et al (67)>	Seveso, Italy male residents>	30,703> total>	1976-1981> 1982-1986> 1976-1986>	TCDD>	RR = 0.70> RR = 1.02> RR = 0.87>
Bertazzi et al (68)>	Seveso, Italy Zone B males>	>	> 1976-1981> 1982-1986> 1976-1986>	TCDD>	RR = 1.47> RR = 2.83> RR = 2.17>
Bertazzi et al (193)>	Seveso, Italy residents> Zone A males> Zone B females> males> Zone R females> males>	>	> 1977-1986>	TCDD>	> RR = 2.7> RR = 1.2> RR = 1.6> RR = 0.6> RR = 1.1>

Table 6-9.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Kidney, other urinary organs (ICD-9 code 189)
Kogan and Clapp (134)	Massachusetts Vietnam veterans	840	1972-83	PH	PMR = 4.0
Bertazzi et al (67)	Seveso, Italy male residents	30,703	1976-1981 1982-1986 1976-1986	TCDD	RR = 0.28 RR = 0.62 RR = 0.48
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.40 SMR = 2.53 SMR = 1.06
Bertazzi et al (193)	Seveso, Italy residents Zone R females males		1977-1986	TCDD	RR = 1.2 RR = 0.9
And other (ICD-9 codes 188, 189.3-189.9)
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.57 - SMR = 1.86

N-Number in population

PH-Phenoxy herbicides

2,4,5-T-2,4,5-Trichlorophenoxy acetic acid

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

CP-Chlorophenols

-No value reported

Although associations of dioxin and Hodgkin's disease (HD) have been reported (233), the studies found conflicting results. In sawmill workers potentially exposed to dioxin, the standardized incidence ratio (SIR) was statistically significantly increased for HD (228); however, exposure to chlorophenols (226) and wood dust (234) potentially confounded this result. Eriksson et al. (228) also reported an elevated risk for HD for physicians and other health care workers; again the results might have been confounded by a concomitant exposure to chlorophenol or contact with a possible HD-associated virus (234). Bertazzi et al. (67,68) also reported a statistically nonsignificant elevation of relative risk for HD in the Seveso adult population. Fingerhut et al. (136,186), however, reported that mortality from HD was not statistically significantly elevated in the U.S. worker cohort.

Recently, NASIOM (59) placed non-Hodgkin's lymphoma (NHL) in group 4, indicating there was sufficient evidence to conclude an association exists between exposure to Agent Orange and NHL. Indeed, the Department of Veterans Affairs (DVA) currently offers compensation for NHL (42). The incidence of NHL was elevated in certain areas around Seveso in the first decade following

Table 6-10.—Brain and nervous system cancers (International Classification of Diseases-9 codes 191, 192) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Brain (ICD-9 code 191)
Bertazzi et al (68)	Seveso, Italy residents Zone R males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 3.60 RR = 0.39 RR = 1.37 RR = 1.23 RR = 6.74 RR = 2.42
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 3.08 RR = 0.34 RR = 1.17 RR = 1.07 RR = 5.83 RR = 2.11
Brain and nervous system (ICD -9 codes 191, 192)
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 0.68 - SMR = 1.06
Bertazzi et al (193)	Seveso, Italy residents Zone R females males		1977-1986	TCDD	RR = 1.4 RR = 0.6

N-Number in population

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

-No value reported

the accident (193). Several case-control studies also found statistically significant fourfold increases in NHL in people reporting exposure to phenoxy acid herbicides or chlorophenols, some of which contained dioxin (226,235,236). Other investigators have also reported a positive association between potential dioxin exposure and NHL (190,212,227,228,232,236-239).

Other investigators have not found a positive association between dioxin exposure and NHL (185,240). In forestry workers, a decreased SIR for NHL was noted (228). In a high exposure subcohort of U.S. workers, the SMRs were statistically nonsignificantly lower for NHL (136,186).

A statistically nonsignificant elevation of relative risk was seen for thyroid gland cancer (Table 6-12) in Seveso (67,68). This was the only study located that investigated thyroid cancer; however, it could be of importance given the outcomes observed in the Dioxin Subregistry population.

Table 6-11.—Lymphatic and hematopoietic tissue cancers (International Classification of Diseases-9 codes 200-208) reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Lymphatic and hematopoietic tissue (ICD-9 codes 200-208)
Zack and Suskind (172)	USA workers (Nitro, WV)	121	1949-78	2,4,5-T	SMR = 3.4
Bertazzi et al (67)	Seveso, Italy residents males   females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.27 RR = 1.16 RR = 0.66 RR = 0.70 RR = 0.74 RR = 0.71
Bertazzi et al (68)	Seveso, Italy Zone B females		1976-1981 1982-1986 1976-1986	TCDD	RR = 1.02 RR = 1.07 RR = 1.04
Manz et al (190)	German male production workers	1,184	1952-87	TCDD	SMR = 1.67
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.09 SMR = 1.02 SMR = 1.25
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males	4,824 total 31,647 total	1977-1986	TCDD	RR = 1.9 RR = 2.1 RR = 0.8 RR = 1.0
Non-Hodgkin's lymphomas (ICD-9 codes 200,202)
Hardell et al (226)	Swedish male agriculture/forestry workers	169	1974-78	PH CP	OR = 4.80 OR = 8.4
Hoar et al (183)	Kansas farm workers with >20 days per year herbicide exposure	200	1976-82	2,4-D, 2,4,5-T	RR = 1.4 RR = 6.0
Pearce et al (227)	Male New Zealand agricultural sprayers	83	1977-81	PH	OR = 1.4
Woods et al (212)	Male Washington state workers farmers forestry sprayers	576	1983-85	PH CP	RR = 1.1 RR = 1.0 RR = 1.3 RR = 4.8
Ott et al (199)	USA manufacturing workers	2,187	1940-82	TCP	O/E = 5/2.6

Table 6-11.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,515 1,520	1942-1984	TCDD	SMR = 1.37 SMR = 1.35 SMR = 0.93
Eriksson et al (228)	Swedish farmers 1960 census 1960 census 1960 census 1970 census 1970 census		1961-1966 1967-1972 1973-1978 1973-1978 1979-1984	PH	SIR = 1.1 SIR = 1.1 SIR = 1.0 SIR = 0.9 SIR = 1.1
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males	4,824 total 31,647 total	1977-1986	TCDD	RR = 0.9 RR = 2.3 RR = 1.2 RR = 1.3
Lynge (181)	Danish production workers	4,459	1982	PH, CP	O/E = 7/5.37
Cantor (229)	Farmers general agriculture small grain farmers wheat farmers	774	1968-76	TCDD	OR = 1.7 OR = 3.2 OR = 6.6 OR = 4.4
Lymphoreticulosarcomas (ICD-9 code 200)
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.42 - SMR = 1.07
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males	4,824 total 31,647 total	1977-1986	TCDD	RR = 2.3 RR = 5.7 RR = 1.7 RR = 1.1
Hodgkin's disease (ICD-9 code 201)
Hoar et al (183)	Kansas farmers Kansas farmers using herbicides	121	1976-82	PH	RR = 0.8 RR = 1.0
Bertazzi et al (67)	Seveso, Italy females		1976-1981 1982-1986 1976-1986	TCDD	RR = 2.07 RR = 5.36 RR = 3.01
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.19 - SMR = 2.76

Table 6-11.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Saracci et al (206)	Sprayers and production workers	18,390		PH, TCDD	SMR = 0.4
Eriksson et al (228)	Swedish farmers 1960 census 1960 census 1960 census 1970 census 1970 census		1961-1966 1967-1972 1973-1978 1973-1978 1979-1984	PH	SIR = 0.9 SIR = 1.1 SIR = 1.1 SIR = 0.8 SIR = 1.4
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males	4,824 total 31, 647 total	1977-1986	TCDD	RR = 2.1 RR = 1.7 RR = 1.0 RR = 1.1
Bertazzi et al (68)	Seveso, Italy residents Zone B males   Zone R females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	- RR = 9.07 RR = 3.76 RR = 2.42 RR = 3.14 RR = 2.65
Pesatori et al (230)	Seveso, Italy children 0-19 years	20,000	1977-1986	TCDD	RR = 2.0
Milham (215)	USA pulp and papermill workers	109		PH	OR = 1.94
Multiple myeloma (ICD-9 code 203)
Bertazzi et al (67)	Seveso, Italy males		1976-1981 1982-1986 1976-1986	TCDD	RR = 0.50 RR = 0.63 RR = 0.55
Bertazzi et al (68)	Seveso, Italy Zone R males		1976-1981 1982-1986 1976-1986	TCDD	RR = 0.58 RR = 0.73 RR = 0.64
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 1.64 - SMR = 2.62
Eriksson et al (228)	Swedish farmers 1960 census 1960 census 1960 census 1970 census 1970 census		1961-1966 1967-1972 1973-1978 1973-1978 1979-1984	PH	SIR = 1.1 SIR = 1.0 SIR = 1.2 SIR = 1.3 SIR = 1.4

Table 6-11.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males	4,824 total 31,647 total	1977-1986	TCDD	RR = 5.3 RR = 3.2 RR = 0.6 RR = 0.2
Leukemias (ICD-9 codes 204-208)
Bertazzi et al (193)	Seveso, Italy children with chloracne males females males with lymphatic leukemia	186		TCDD	RR = 2.9 RR = 2.5 RR = 9.6
Saracci et al (206)	IARC cohort, chemical workers with 10-19 years latency exposed not exposed	18,390		PH, TCDD	RR = 1.2 RR = 0.9
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency, ³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 0.67 SMR = 1.26 SMR = 0.77
Bertazzi et al (67)	Seveso, Italy residents males females	30,703	1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	RR = 0.31 RR = 1.39 RR = 0.70 RR = 0.73 RR = 0.26 RR = 0.50
Bertazzi et al (68)	Seveso, Italy residents Zone A males   Zone B males   females		1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986 1976-1981 1982-1986 1976-1986	TCDD	- - RR = 1.98 RR = 1.36 RR = 4.89 RR = 2.44 RR = 0.56 RR = 0.30 RR = 0.43
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males	4,824 total 31,647 total	1977-1986	TCDD	RR = 1.8 RR = 1.6 RR = 0.4 RR = 0.9

Table 6-11.—Continued.

Investigators	Population	N	Date(s)	Exposure	Results
Myeloid leukemia (ICD-9 code 205)
Bertazzi et al (67)	Seveso, Italy male residents		1976-1981 1982-1986 1976-1986	TCDD	RR = 1.57 RR = 4.23 RR = 2.53
Bertazzi et al (68)	Seveso, Italy Zone R males		1976-1981 1982-1986 1976-1986	TCDD	RR = 0.91 RR = 4.90 RR = 2.36
Bertazzi et al (193)	Seveso, Italy residents Zone B females males Zone R females males	4,824 total 31,647 total	1977-1986	TCDD	RR = 3.7 RR = 2.0 RR = 0.5 RR = 1.4
Wiklund et al (185)	Swedish pesticide applicators	20,245	1984	PH	no excess
Wiklund et al (231)	Swedish workers farmers foresters	354,620	1984	PH	4.5-fold 2.3-fold
Pesatori et al (230)	Seveso, Italy children 0 - 19 years	20,000	1977-1986	TCDD	RR = 2.7

N-Number in population

PH-Phenoxy herbicides

2,4-D-2,4-Dichlorophenoxy acetic acid

2,4,5-T-2,4,5-Trichlorophenoxy acetic acid

TCP-Trichlorophenol

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

SIR-Standardized incidence ratio

CP-Chlorophenols

OR-Odds ratio

-No value reported

Bone and joint cancers are relatively uncommon; therefore the cohorts are usually too small for meaningful analyses-even one case may give an apparent excess of risk. The NASIOM (59) has concluded there is inadequate/insufficient evidence to evaluate an association between this cancer and dioxin exposure.

The carcinogenicity of dioxin has been demonstrated in several animal species (243-245); however, carcinogenicity studies have been difficult to perform since the maximum tolerated dose is very low because of the extreme toxicity of the substance. The cancers reported have included tumors of the liver, palate, lung, and nasal mucosa (99); hepatocellular carcinomas; cholangiocarcinomas; and bile duct neoplasms, as well as neoplasms of the skin, lung, palate, tongue, and thyroid (54,80,166,246-248).

Table 6-12.—Other cancers reported in epidemiological studies of human exposure to dioxin.

Investigators	Population	N	Date(s)	Exposure	Results
Bone (ICD-9 code 170)
Coggon et al (63)	British MPCA production workers	5,754	1947-83		RR = 0.9
Wiklund (241)	Swedish agricultural workers	19,490	1961-73		RR = 1.0
Breslin et al (242)	Army Vietnam veterans Marine Vietnam veterans	24,235 total	1965-82		RR = 0.8 RR = 1.4
Fingerhut et al (186)	USA workers ³20 years latency, <1 year exposure ³20 years latency,³1 year exposure	5,172 1,516 1,520	1942-1984	TCDD	SMR = 2.27 - SMR = 5.21
Thyroid (ICD-9 code 193)
Bertazzi et al (67)	Seveso, Italy female residents		1976-1981 1982-1986 1976-1986	TCDD	RR = 2.24 RR = 2.96 RR = 2.44
Pesatori et al (230)	Seveso children 0-19 years of age		1977-86	TCDD	RR = 4.6
Bertazzi et al (193)	Seveso, Italy residents Zone R females males		1977-1986	TCDD	RR = 1.7 RR = 0.7

N-Number in population

SMR-Standardized mortality ratio

TCDD-2,3,7,8-tetrachlorodibenzo-p-dioxin

RR-relative risk ratio

-No value reported

The generation of tumors in a number of organs in animals exposed to dioxin and the demonstration that dioxin promoted tumors in two organs (168,248) make it biologically plausible that dioxin could produce tumors in more than one organ in humans. To date, conflicting evidence seems to indicate that dioxin is not a potent mutagen (249,250); however, dioxin is a tumor promoter. Poland et al. (168) found that dioxin produced a statistically significant increase in the incidence of skin tumors in mice pretreated with a single dose of a potent initiator. Dioxin also enhances the metabolic activation of certain procarcinogens, such as benzo(a)pyrene (251). Dioxin promotes diethylnitrosamine-initiated liver tumors in rats and also dimethylbenzanthracene- or methyl-n-nitrosoguanidine-initiated skin tumors in hairless mice (252). Thus, dioxin might not cause site-specific cancers, but rather act at those tissue sites where cells have been transformed by the prior action of initiators or mutagens (49).

Since dioxin has been shown to have a relative lack of ability to either covalently bind to DNA or to induce DNA repair synthesis, dioxin carcinogenesis is probably a nongenetic mechanism. The higher incidence of liver tumors in female rats dosed with dioxin can at least in part be explained by the interaction of dioxin with the estrogen receptor in liver cells (253). In addition, liver cell necrosis noted in the study by Kociba et al. (99) might be a potentiating factor for tumor development. Furthermore, if the estrogen receptor is involved and if liver cell necrosis is a factor, then the response at lower doses would no longer be linear but might actually drop off sharply. Some evidence of this can be seen in the observation that hormone-dependent tumors of the mammary gland, cervix, and pituitary were actually reduced in incidence by chronic dioxin exposure (99).

In conclusion, the findings of excess cancer in the Dioxin Subregistry do have direct support in the literature; however, the specific types of cancer found in the Subregistry are not those commonly associated with dioxin exposure. Ascertainment of cases will be an important first step in investigation of these cancers and their potential relationship, if any, to dioxin exposure.

SUMMARY

This section has reviewed the most current scientific literature for dioxin exposure and health effects. The literature suggests that there might be associations between dioxin exposure and some of the health outcomes that are reported in excess by the Subregistry data. The reported literature has many limitations: case reports of occupational studies usually involve only males; exposure levels in occupational exposures are much higher than those reported in environmental exposures; high-dose animal studies might not be relevant to humans; and human health studies often lack sufficient exposure characterization, controls for important confounding factors, and sample sizes large enough to investigate low-dose effects. These and other limitations must be considered by the reader. This section does not support a cause and effect relationship between dioxin exposure and human health outcomes. However, interesting areas for further investigation are mentioned.

SECTION 7

CONCLUSIONS AND RECOMMENDATIONS

CONCLUSIONS

The Dioxin Subregistry population reported more often for some adverse health outcomes at Baseline and Followups 1 and 2 when compared with the appropriate national survey. Statistically significantly increased reporting for the Subregistry population at Baseline and each Followup was found for all Dioxin Subregistry members, in some cases for all or select age and sex groups, for the health conditions stroke, anemia and other blood disorders, urinary tract infections, skin rashes, and cancer; at Baseline and Followup 2 for stroke and cancer; at Baseline only for anemia and other blood disorders. In all cases, the reporting was increased over the National Health Interview Survey (NHIS) for these conditions.

Of concern are the excess numbers of reported cardiovascular problems, that is, stroke and anemia or other blood disorders. Cardiovascular conditions continue to be major contributors to disease and death in the United States, yet many of the underlying factors that contribute to these outcomes have yet to be identified. The findings of the Subregistry suggest that studies are needed to determine if exposure to dioxin might contribute to the development of these conditions. More information from registrants on potentially confounding factors, such as diet, specific health risk behaviors (such as smoking and alcohol consumption), and other lifestyle factors, along with the analyses of the follow-up data for the Dioxin Subregistry population, will help identify the contributing factors. In addition, future studies of this population should focus on validating of these findings and exploring if a dioxin exposure-health outcome linkage exists.

Statistically significantly decreased reporting by the Dioxin Subregistry members when compared with the NHIS population was found for the conditions arthritis, hearing impairments, and respiratory allergies. This finding was expected, given that these are often self-diagnosed health conditions and would, therefore, be most affected by the limitations of health care provider confirmation by the registrants but not the NHIS respondents.

Limitations of the comparison of the Dioxin Subregistry data with NHIS data must be kept in mind when interpreting the results. The comparability of the questions (some questions were very closely worded, others were similar), recall bias (exposed people were perhaps more aware of health problems and remembered events in greater detail), and frequency of health care utilization (exposed people were perhaps more aware of health problems and sought health care more often) must be considered when interpreting the results in light of reported national norms. Because of the many comparisons carried out, some of the positive results might have been chance occurrences, or might have occurred because the true causal factors (confounders) were not identified. Also, the small sample size is of concern.

Individual dose estimates will be considered in the future for the Dioxin Subregistry population. Recently, several computer models have become available with which general exposure patterns can be simulated with a minimum amount of information. Perhaps these models could be used in conjunction with statistical models to develop a best estimate of environmental levels for all exposure periods and sites. If this is shown to be feasible, individual doses might be reconstructed for all routes of exposure for further use in dose-response evaluations.

RECOMMENDATIONS

Cause and effect relationships cannot be determined from the analyses conducted on the Subregistry-based information. Information obtained from this database can and will be used to determine appropriate future activities and research. Research related to modification of the current data collection procedures and methods and exploration of recognized sources of bias and reduction or elimination of these biases is occurring.

It is unclear whether either wording differences between Dioxin Subregistry and NHIS questions or recall bias might have generated different response rates. In order to better understand the possible excess reporting of some of the health conditions, the Agency for Toxic Substances and Disease Registry (ATSDR) is conducting an evaluation of how these wording differences could have created differences in responses and will modify the questions appropriately for future Subregistry activities. New methods are being considered that could aid in assessing the potential impact of exposure awareness on both the recall of health conditions and health care utilization by registrants. It should be noted that even if a determination is made that exposed people sought health care more often, it would not be possible to separate whether the increase in number of visits was due to an awareness of exposure or from an actual increase in health problems.

Improvement of individual exposure estimates for the Dioxin Subregistry population and other environmentally exposed populations is a top priority for ATSDR. Better exposure characterization of registrants would allow improved assessment of the relationship between exposure and health outcomes. This is being explored.

Preliminary findings from the completed analyses leave many questions unanswered; hopefully, additional information and further investigations will help answer these questions. In addition, acquisition of definitive information on and confirmation of selected outcomes that appear to be in excess and substance-specific research with specific hypotheses clearly identified will be considered for this Subregistry. Longitudinal following of the Dioxin registrants will continue on a routine basis. The additional information collected will be used to assess trends in reporting and to assist in answering or clarifying some of the issues and questions previously discussed.

It should be noted that most of the health conditions that were reported in excess by the Dioxin Subregistry population are preventable or treatable, if not curable. Early detection frequently plays a role in whether a health condition can be arrested or reversed by existing medical technologies. Given the results of the Baseline analyses for this population, it was imperative that this information be shared with dioxin-exposed persons in a responsible manner.

A summary version of the Dioxin Subregistry Baseline Technical Report will be composed in nontechnical language for release to the registrants. A Subregistry Technical Assistance Panel (STAP), which will be composed of representative membership from the states involved, other federal agencies, and other knowledgeable persons, will review the Dioxin Subregistry Baseline Technical Report and the registrant report and give ATSDR suggestions and recommendations as to future activities that would be appropriate for followup to release of the information.

Following review of the registrant report by the STAP, community representatives, along with interested county, state, and federal agency representatives, will meet to review the report and to assist ATSDR with planning site-specific activities and developing a one-page fact sheet summarizing the report. Immediately following these meetings, information packets containing the registrant report, fact sheet, and cover letter will be mailed to all Dioxin Subregistry members. Similar information will be mailed to the media shortly after the registrants receive their information packets.

Public meetings will be held in each of the areas with Dioxin Subregistry sites. The public meetings will be conducted to review the purpose of the Dioxin Subregistry and the information provided to the registrants. Registrants will be encouraged to ask questions of ATSDR, either in person or by telephone. Those registrants expressing specific health concerns will be encouraged to see their personal physicians. A concerted effort will be made by ATSDR to share the findings of the Baseline Dioxin Subregistry analyses with the appropriate health care providers in each area. In addition, specific information about dioxin and training will be made available to them.

Although no definitive conclusions can be made from the information contained in this report, it is hoped that researchers will use the information to better assess the potential for adverse health outcomes following exposure to dioxin in the environment. As pointed out, additional studies of the Dioxin Subregistry data are warranted and encouraged by ATSDR.

EXECUTIVE SUMMARY

This is a report on the data collection activities and results of the statistical analyses of the baseline and first and second follow-up data for the Dioxin Subregistry of the National Exposure Registry. The National Exposure Registry was created in response to the congressional mandate detailed in the 1980 Comprehensive Environmental Response, Compensation, and Liability Act and reiterated in the Superfund Amendments and Reauthorization Act of 1986. This mandate directed the Agency for Toxic Substances and Disease Registry (ATSDR) to create a registry of people exposed to hazardous substances in the environment. The Dioxin Subregistry is one of three chemical-specific subregistries currently contained in the National Exposure Registry.

As with the other subregistries in the National Exposure Registry, the Dioxin Subregistry is a database containing information on people who have been exposed to a specific chemical, in this case dioxin. The purpose of the Registry is to assess the long-term health consequences, if any, of long-term exposure to low levels of hazards (usually chemicals) in the environment. It should be noted that the Registry itself is not a definitive study; cause-effect relationships cannot be established using only Registry-based information. However, the Registry will furnish the information needed to generate appropriate and valid hypotheses for future activities-such as epidemiologic studies.

The data collected for each member of the Dioxin Subregistry include demographic information, smoking and occupational histories, and self-reported responses to 25 general health status questions. The data files for each subregistry are established at the time baseline data are collected. A follow-up survey is conducted 1 year after baseline data collection, and surveys are, in most cases, conducted at 2-year intervals after that to update the data files. For the Dioxin Subregistry, all interviews were conducted by means of computer-assisted telephone interviewing.

The Dioxin Subregistry contains information on 250 persons (246 living at the time of Baseline data collection and 4 deceased; 221 living at the time of Followup 1 data collection and 5 deceased [1 additional]; and 203 living at the time of Followup 2 data collection and no additional deceased) who had participated in at least one of four specific health studies previously conducted at dioxin-contaminated sites in Missouri. These individuals were reportedly exposed at one of four of the Times Beach, Missouri, area dioxin sites. For eligible people who were deceased, death certificates were obtained and pertinent information abstracted. The participation rate for those individuals identified as eligible and contacted was 91% at Baseline, 96% at Followup 1, and 96% at Followup 2.

For each of the Dioxin Subregistry databases-Baseline, Followup 1, and Followup 2-the rate of reporting for each health outcome was calculated and compared with national norms-rates calculated using the corresponding annual National Health Interview Survey (NHIS). A statistically significant difference in reporting by the registrants and the NHIS respondents was found for several health conditions. Most differences were consistent across the Baseline and Followup databases. A statistically significant increase in reporting was found for all registrants or specific sex-age subgroups for the following health outcomes: cancers (all) (Baseline, Followup 2); skin rash (Baseline, Followups 1 and 2); stroke (Baseline, Followup 2); urinary tract disorders (Baseline, Followups 1 and 2); and anemia (Baseline, Followup 2). A statistically significant decrease in reporting by the registrants was found for all or specific sex-age subgroups for hearing impairment (Baseline, Followups 1 and 2); respiratory allergies (Baseline); and arthritis (Followup 2).

The statistical findings in this report are suggestive of possible associations between dioxin exposure and adverse health outcomes; a causal relationship was not confirmed. When interpreting the findings, the small Subregistry population, methodological differences, restrictions, and possible biases must be taken into account; for example, because of the knowledge of their exposure, registrants might have sought medical care more often than the general population; a small subset of the health questions in the Dioxin Subregistry questionnaire were worded slightly differently than corresponding questions in the NHIS questionnaire; and the restriction of needing health care provider confirmation for a reported health condition was placed on registrants only. Finally, the smoking rates in the Dioxin Subregistry population were elevated, possibly influencing tobacco use-related disease rates. These limitations and biases, along with others discussed in detail in the report, must be considered when comparing the reported rates.

The findings of this report do reinforce the need to continue followup of this population on a regular basis. In addition, the findings suggest several areas needing further study or clarification.

• New methods need to be explored to characterize the environmental exposures of registrants. Dose-response relationships need to be further explored by means of strategies currently being investigated by ATSDR.
• For those health outcomes reported in excess by the Dioxin Subregistry population, additional information is needed for those people responding positively. The types of information that might prove useful include further details of health conditions from medical files, information on lifestyle factors (such as alcohol consumption or diet), or more complete information on occupational exposures that might relate to another potentially causative factor. In the future, ATSDR plans to contact registrants to obtain their permission to access all or part of this information. These data, along with the data obtained from the continued followup of the registrants and confirmation of medical conditions, will aid in further exploration of suggested linkages.
• The wording of Subregistry questions will be altered to more closely align them with the corresponding NHIS questions.
• The data file, without personal identifiers, will be made available to the public. Other researchers are encouraged to study these reported results more extensively and to explore other analyses.

Another of the stated goals of the National Exposure Registry is to keep registrants informed of all current information related to their exposures. Before release of the information in this report, a Dioxin Subregistry Technical Assistance Panel-composed of representative membership from the states involved, other federal agencies, and other knowledgeable people-will be formed and advice solicited from the members on the process of information release and on future research needs. Following the panel meeting and immediately before the release of information to the registrants, a meeting with community officials, along with interested county, state, and federal agency representatives, will be held to plan any site-specific activities-including public meetings. A registrant report, written for the general public and containing the findings of this technical report, will be prepared and sent to each registrant. The registrant report will then be released to the media. The mailing will be followed by a public meeting at each site to discuss the report.

REFERENCES

1. Agency for Toxic Substances and Disease Registry. Policies and procedures for establishing a national registry of persons exposed to hazardous substances: national exposure registry. Atlanta: US Department of Health and Human Services, Public Health Service, 1988.
2. Agency for Toxic Substances and Disease Registry. National Exposure Registry-Policies and procedures manual (revised). Atlanta: US Department of Health and Human Services, Public Health Service, 1994.
3. Roberts DW, Bagby JR. Report on cooperative agreement special investigations study U61/CCU700735-01 - reproductive outcomes in pregnant women potentially exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Jefferson City, Missouri: Missouri Department of Health, 1987.
4. Missouri Department of Health. Missouri dioxin health studies, progress report. Missouri Division of Health, The Centers for Disease Control, St. Joseph's Hospital of Kirkwood, St. Louis University Hospital. October 16, 1983.
5. Agency for Toxic Substances and Disease Registry. Hazardous substances priority list, toxicological profiles, second list. Federal Register 1988;53:41280.
6. Agency for Toxic Substances and Disease Registry. Toxicological profile for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Atlanta: US Department of Health and Human Services, Public Health Service, 1989.
7. Dioxin briefing for the Missouri Delegation by Morris Kay, EPA Regional Administrator, Region VII, September 13, 1983.
8. Powell RL. Dioxin in Missouri: 1971-1983. Bull Environ Contam Toxicol 1984; 33:648-54.
9. Stehr PA, Stein GF, Webb K, Schramm W, Gedney WB, Donnell HD, et al. A pilot epidemiologic study of possible health effects associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin contaminations in Missouri. Arch Environ Health 1986;41:16-22.
10. Hoffman RE, Stehr-Green PA, Webb KB, Evans RG, Knutsen AP, Schramm WF, et al. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. JAMA 1986;255:2031-38.
11. Roberts DW, Bagby JR. Report on cooperative agreement special investigations study U61/CCU700563-02 - Missouri dioxin study. Jefferson City, Missouri: Missouri Department of Health, 1987.
12. Macdonald JR. Quail Run, Gray Summit, Missouri, On-Scene Coordinator final report. March 3, 1988.
13. Agency for Toxic Substances and Disease Registry. Health consultation: Quail Run site, Gray's Summit, Missouri. Atlanta: US Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, 1990 Sep 14.
14. Ruelle R. Proposed study to determine dioxin presence and levels in selected biota within Missouri, Resource Containment Assessment. Rock Island, Illinois: US Fish and Wildlife Service, September 1984.
15. National Center for Health Statistics. Public use data tape documentation, part I, National Health Interview Survey, 1989 (Machine readable data file documentation). Springfield (VA): US Department of Commerce, National Technical Information Service, 1990.
16. National Center for Health Statistics. Current estimates from the National Health Interview Survey, United States, 1989. Vital and health statistics; series 10, no. 164. Washington, DC: US Department of Health and Human Services, Public Health Service, 1990.
17. Rosner B. Fundamentals of biostatistics, 3rd edition. Boston: PWS-KENT, 1990.
18. Rothman KJ. Modern epidemiology. Boston: Little, Brown, and Co., 1986.
19. Agresti A. Categorical data analysis. New York: John Wiley & Sons, Inc., 1990.
20. Sweet JA, Bumpass LL. American families and households. New York: Russell Sage, 1987.
21. Aday LA, Anderson R. The national profile of access to medical care: where do we stand? Am J Public Health 1985;74:12.
22. Alcohol, Drug Abuse, and Mental Health Administration. National household survey on drug abuse 1990 population estimates. Washington, DC: US Department of Health and Human Services, Public Health Service, 1991. Publication (ADM) 91-1732.
23. National Center for Health Statistics. Public use data tape documentation, part I, National Health Interview Survey, 1990 (Machine readable data file documentation). Springfield (VA): US Department of Commerce, National Technical Information Service, 1991.
24. Centers for Disease Control. Behavioral risk-factor surveillance, 1986-1990. MMWR 1991;40:1-24.
25. World Health Organization. International classification of diseases: manual of the international statistical classification of diseases, injuries, and causes of death. Geneva: World Health Organization, 1977.
26. Lipscomb JA, Satin KP, Neutra RR. Reported symptom prevalence rates from comparison populations in community-based environmental studies. Arch Environ Health 1992;47:4.
27. Breslow NE, Day NE. Statistical methods in cancer research, vol. 2. The design and analysis of cohort studies. Lyon: International Agency for Research on Cancer, 1987.
28. Centers for Disease Control & Prevention. Cigarette smoking among adults, United States, 1988. MMWR 1991;40:757-9.
29. Shopland DR, Niemcryk SJ, Marconi KM. Geographic and gender variations in total tobacco use. Am J Public Health 1992;82:103-6.
30. National Cancer Institute. Surveillance, epidemiology and end results program (SEER) data. Bethesda (MD): National Cancer Institute, Cancer Statistics Branch, 1989.
31. National Center for Health Statistics. Public use data tape documentation, part I, National Health Interview Survey, 1991 (Machine readable data file documentation). Springfield (VA): US Department of Commerce, National Technical Information Service, 1992.
32. Centers for Disease Control. Cigarette smoking-attributable mortality and years of potential life lost-United States, 1990. MMWR 1991;42:645-9.
33. Umbreit TW, Hesse EJ, Gallo MA. Bioavailability of dioxin in soil from a 2,4,5-T manufacturing site. Science 1986;232:497-9.
34. McConnell EE, Lucier GW, Rumbaugh RC, Albro PW, Harvan DJ, Hass JR, et al. Dioxin in soil: bioavailability after ingestion by rats and guinea pigs. Science 1984;223:1077-9.
35. Pocchiari F, DiDomenico A, Silano V, Zapponi G. Environmental impact of the accidental release of TCDD at Seveso (Italy). In: Coulston F, Pocchiari F, editors. Accidental exposure to dioxin. New York: Academic Press, 1983:5-37.
36. Miller GC, Herbert VR, Mille M, Mitzel R, Zepp R. Photolysis of octachlorodibenzo-p-dioxin on soils: production of 2,3,7,8-TCDD. Chemosphere 1989;18:1265-74.
37. Council on Scientific Affairs. Health effects of Agent Orange and dioxin contaminants. JAMA 1982;248:1895-7.
38. Kahn PC, Gochfeld M, Nygren M, Hansson M, Rappe C, Velez H, et al. Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam veterans and matched controls. JAMA 1988;259:1661-7.
39. Pirkle JL, Wolfe WH, Patterson DG, Needham LL, Michalek JE, Miner JC, et al. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand. J Toxicol Environ Health 1989;27:165-71.
40. Poiger H, Schlatter C. Pharmacokinetics of 2,3,7,8-TCDD in man. Chemosphere 1985;15:1489-94.
41. Gallo MA, Scheuplein RJ, van der Heijden KA. Biological basis for risk assessment of dioxins and related compounds. Banbury Report 1991;35.
42. Hanson DJ. Dioxin toxicity; new studies prompt debate, regulatory action. Chemical and Engineering News 1991;August 12:7-14.
43. Orban JE, Stanley JS, Schwemberger JG, Remmers JC. Dioxins and dibenzofurans in adipose tissue of the general US population and selected subpopulations. Am J Public Health 1994;84:439-445.
44. Kimbrough RD. How toxic is 2,3,7,8-tetrachlorodibenzo-p-dioxin to humans? J Toxicol Environ Health 1990;30:261-73.
45. Stanley JS. Broad scan analysis of human adipose tissue. In Vol 4, Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Final report prepared for the Office of Toxic Substances of the US Environmental Protection Agency under Contract No. 68-02-4252. EPA 560/5-86-038. 1986.
46. Pluim HJ, Wever J, Koppe JG, van der Slikke JW, Olie K. Intake and faecal excretion of chlorinated dioxins and dibenzofurans in breast-fed infants at different ages. Chemosphere 1993;26:1947-52.
47. Pluim HJ, van der Slikke JW, Olie K, van Velzen MJM, Koppe JG. Dioxins and vitamin K status of the newborn. J Environ Sci Health 1994;A29:793-802.
48. Pluim HJ, Koppe JG, Olie K, van der Slikke JW, Slot PC, van Boxtel CJ. Clinical laboratory manifestations of exposure to background levels of dioxins in the perinatal period. Acta Paediatr 1994;83:583-7.
49. Silbergeld EK, Gasiewicz TA. Dioxins and the Ah receptor. Am J Ind Med 1989;16:455-74.
50. Moore JA. Toxicity of 2,3,7,8-tetrachlorodibenzo-para-dioxin. In: Ramel C, editor. Chlorinated phenoxy acids and their dioxins, ecological bulletin 27. Stockholm: Swedish Natural Science Research Council, 1978:133-44.
51. Kimbrough RD, Falk H, Stehr P, Fries G. Health implications of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) contamination of residential soil. J Toxicol Environ Health 1984;14:47-93.
52. Anon. Officials say dangers of dioxin were exaggerated. National Environmental Journal 1992;Jan/Feb: 58.
53. Poland A, Glover E, Kende AS. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol: evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem 1976;251:4936-46.
54. Poland A, Knutson JC. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annual Review of Pharmacology and Toxicology 1982;22:517-54.
55. Hoffman EC, Reyes H, Chu F-F, Sander F, Conley LH, Brooks BA, Hankinson O. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 1991;252:954-8.
56. Reyes H, Reiz-Porszasz S, Hankinson O. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science 1992;256:1193-5.
57. National Institute for Environmental Health Sciences. Challenging a dioxin hypothesis. Environ Health Perspect 1993;101:393-4.
58. Kimbrough RD, Carter CD, Liddle JA, Cline RE, Phillips PE. Epidemiology and pathology of a 2,3,7,8-tetrachlorodibenzo-p-dioxin poisoning episode. Arch Environ Health 1977;3:77-85.
59. National Academy of Sciences, Institute of Medicine. Veterans and Agent Orange. Health effects of herbicides used in Vietnam. Washington, DC: National Academy Press, 1994.
60. Suskind RR, Hertzberg VS. Human health effects of 2,4,5-T and its toxic contaminants. JAMA 1984;251:2372-80.
61. Kociba R, Keyes DG, Beyer JE, Carreon RM, Gehring PJ. Long term toxicologic studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in laboratory animals. Ann N Y Acad Sci 1979;320:397-404.
62. Anderson HA, Hanrahan LP, Jensen M. Wisconsin Vietnam Mortality Study, Final Report. Madison: State of Wisconsin Department of Health and Social Services, Division of Health, 1986.
63. Coggon D, Pannett B, Winter PD, Acheson ED, Bonsall J. Mortality of workers exposed to 2-methyl-4 chlorophenoxyacetic acid. Scand J Work Environ Health 1986;12:448-54.
64. Coggon D, Pannett B, Winter P. Mortality and incidence of cancer at four factories making phenoxy herbicides. Br J Ind Med 1991;48:173-8.
65. Blair A, Grauman DJ, Lubin JH, Fraumeni JF Jr. Lung cancer and other causes of death among licensed pesticide applicators. J Natl Cancer Inst 1983;71:31-7.
66. Alavanja MC, Merkle S, Teske J, Eaton B, Reed B. Mortality among forest and soil conservationists. Arch Environ Health 1989;44:94-101.
67. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. Mortality in an area contaminated by TCDD following an industrial incident. Med Lav 1989; 80:316-29.
68. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. Ten-year mortality study of the population involved in the Seveso incident in 1986. Am J Epidemiol 1989;129:1187-200.
69. Boyle C, Decoufle P, Delaney RJ, DeStefano F, Flock ML, Hunter MI, Joesoef MR, et al. Postservice mortality among Vietnam veterans. Atlanta: Centers for Disease Control, 1987;1-143. Publication no. CEH 86-0076.
70. CDC. Centers for Disease Control Vietnam Experience Study. Postservice mortality among Vietnam veterans. JAMA 1987;257:790-5.
71. CDC. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in US Army Vietnam-era veterans. Centers for Disease Control. JAMA 1988;260:1249-54.
72. Fett MJ, Nairn JR, Cobbin DM, Adena M. Mortality among Australian conscripts of the Vietnam conflict era. II. Causes of death. Am J Epidemiol 1987;125:878-84.
73. Watanabe K, Kang H, Thomas T. Mortality among Vietnam veterans: with methodologic considerations. J Occup Med 1991;33:780-5.
74. Eisen S, Goldberg J, True WR, Henderson WG. A co-twin control study of the effects of the Vietnam War on the self-reported physical health of veterans. Am J Epidemiol 1991;134:49-58.
75. Stellman SD, Stellman JM, Sommer JF Jr. Health and reproductive outcomes among American Legionnaires in relation to combat and herbicide exposure in Vietnam. Environ Res 1988;47:150-74.
76. Roegner RH, Grubbs WD, Lustik MB, Brockman AS, Henderson SC, Williams DE, et al. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides, serum dioxin analysis of 1987 examination results. Brooks Air Force Base, March 1991.
77. Calvert GM, Sweeney MH, Morris JA, Fingerhut MA, Hornung RW, Halperin WE. Evaluation of chronic bronchitis, chronic obstructive pulmonary disease, and ventilatory function among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Am Rev Respir Dis 1991;144:1302-6.
78. NCI/NTP. Bioassay of a mixture of 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (gavage) for possible carcinogenicity: CAS No. 57653-85-7, CAS No. 19408-74-3. Research Triangle Park, NC: US Department of Health and Human Services, Public Health Service, National Institutes of Health/National Toxicology Program, 1980. NCI Carcinogen Tech Rep Ser no. 198. NTP no. 80-12.
79. Allen JR, Barsotti DA, Van Miller JP, Abrahamson LJ, Lalich JJ. Morphological change in monkeys consuming a diet containing 500 ppt of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Food Cosmet Toxicol 1977;15:401-10.
80. NTP. Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Swiss-Webster mice (dermal study). Washington, DC: National Toxicology Program, 1982. Publication no. (NTP) 80-32.
81. NCI/NTP. Bioassay of dibenzo-p-dioxin for possible carcinogenicity. Bethesda, MD: US Department of Health, Education, and Welfare, Public Health Service, National Cancer Institutes/National Toxicology Program, 1979. (NIH) DHEW Publication no. 79-1377.
82. Webb KB. The pilot Missouri health effects study. Bull Environ Contam Toxicol 1984;33:662-72.
83. Scientific Review Committee of the American Academy of Clinical Toxicology. Commentary on 2,3,7,8-tetrachlorodibenzo-p-dioxin. Clin Toxicol 1985;23:191-204.
84. Jennings AM, Wild G, Ward JD, Ward AM. Immunological abnormalities 17 years after accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Br J Ind Med 1988;45:701-4.
85. Koppe JG, Pluim E, Olie K. Breastmilk, PCBs, dioxins and vitamin K deficiency: discussion paper. J Royal Soc Med 1989;82:416-9.
86. Poland A. Induction of the drug-metabolizing enzymes. In: Bartsch H, Armstrong B, editors. IARC Scientific Publications no. 39. Lyon: International Agency for Research on Cancer, 1982.
87. World Health Organization (WHO). Environmental health. Report WHO. July 1988; i:8520.
88. Bouwman CA, Fase K, Koppe JG, Seinen W, van der Berg M. Effects of 2,3,7,8-TCDD or 2,2',4,4',5,5'-HxCB on activity of the vitamin K-cycle enzymes in rats: a novel mechanism of action. In: Organohalogen compounds, vol. 10. Tampere, Finland:Dioxin '92 Congress, 1992.
89. McConnell EE, Moore JA, Dalgard DW. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rhesus monkey (Macaca mulatta) following a single oral dose. Toxicol Appl Pharmacol 1978;43:175-87.
90. Greenlee WF, Osborne R, Hudson LG, Toxcano WA Jr. Studies on the mechanisms of toxicity of TCDD to human epidermis. Banbury Report 1984;18:365-72.
91. Thigpen JE, Faith RE, McConnell EE. Increased susceptibility to bacterial infection as a sequela of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Infect Immunol 1975;12:1319-24.
92. Hanberg A, Hakansson H, Ahlborg UG. "ED50"values for TCDD-induced reduction of body weight gain, liver enlargement, and thymic atrophy in Hartley guinea pigs, Sprague-Dawley rats, C57BL/6 mice, and golden Syrian hamsters. Chemosphere 1989;19:813-6.
93. Silkworth JB, Cutler DS, Antrim L, Houston D, Tumasonis C, Kaminsky LS. Teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin in a complex environmental mixture from Love Canal. Fundam Appl Toxicol 1989;13:1-15.
94. Holladay SD, Lindstrom P, Blaylock BL, Comment CE, Germolec DR, Heindell JJ, et al. Perinatal thymocyte antigen expression and postnatal immune development altered by gestational exposure to tetrachlorodibenzo-p-dioxin (TCDD). Teratology 1991;44:385-93.
95. Umbreit TH, Patel D, Gallo MA. Acute toxicity of TCDD contaminated soil from an industrial site. Chemosphere 1985;14:945-7.
96. Vos JG, Moore JA, Zinkl JG. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the immune system of laboratory animals. Environ Health Perspect 1973;5:149-62.
97. Murray FJ, Smith FA, Nitschke KD, Humiston CG, Kochiba RJ, Schwetz BA. Three-generation reproduction study of rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Toxicol Appl Pharmacol 1979;50:241-51.
98. DeCaprio AP, McMartin DM, O'Keefe PW, Rej R, Silkworth JB, Kaminsky LS. Subchronic oral toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the guinea pig: comparisons with a PCB-containing transformer fluid pyrolysate. Fundam Appl Toxicol 1986;6:454-63.
99. Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Wade CE, Dittenber DA, et al. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol Appl Pharmacol 1978;46:279-303.
100. McConnell EE. Acute and chronic toxicity, carcinogenesis, reproduction, teratogenesis, and mutagenesis in animals. In: Kimbrough RD, editor. Halogenated biphenyls, terphenyls, naphthalenes, dibenzodioxins and related products. Amsterdam: Elsevier/ North Holland, 1980:109-50.
101. McNulty W. Fetotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for Rhesus macaques (Macaca mulatta). Am J Primatol 1984;6:41-7.
102. Birnbaum LS, Harris MW, Stocking LM, Clark AM, Morrisey RE. Retinoic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin selectively enhances teratogenesis in C57BL/6N mice. Toxicol Appl Pharmacol 1989;98:487-500.
103. Weissberg JB, Zinkl JG. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin upon homeostasis and hematologic function in the rat. Environ Health Perspect 1973;5:119-23.
104. Zinkl JG, Vos JG, Moore JA, Gupta BN. Hematologic and clinical chemistry effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals. Environ Health Perspect 1973;5:111-8.
105. Luster MI, Hong LH, Boorman GA, Clark G, Hayes HT, Greenlee WF, et al. Acute myelotoxic responses in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol 1985;81:156-65.
106. Oliver RM. Toxic effects of 2,3,6,8-tetrachlorodoxin-p-dibenzo 1,4-dioxin in laboratory workers. Br J Ind Med 1975;32:49-53.
107. Jirasek L, Kalensky J, Kubeck K, Pazderova J, Lukas E. Acne chlorina, porphyria cutanea tarda and other manifestations of general intoxication during the manufacture of herbicides, part 2. Cesk Dermatol 1974;49:145-57.
108. Butler MG. Acneiform dermatosis produced by ortho (2 chlorophenyl) phenol sodium and tetrachlorophenol sodium. Arch Dermatol Syph 1937;35:251-4.
109. Kimmig J, Schulz KH. Occupational chloracne caused by aromatic cyclic ethers. Dermatologica 1957;115:540-6.
110. Reggiani G. Medical problems raised by the TCDD contamination in Seveso, Italy. Arch Toxicol 1978;40:161-88.
111. Ashe W, Suskind RR. Chloracne cases of the Monsanto Chemical Company. Nitro, West Virginia. In: Reports of the Kettering Laboratory. University of Cincinnati, October 1949.
112. Ashe W, Suskind RR. Chloracne cases of the Monsanto Chemical Company. Nitro, West Virginia. In: Reports of the Kettering Laboratory. University of Cincinnati, April 1950.
113. Ashe W, Suskind RR. Chloracne cases of the Monsanto Chemical Company. Nitro, West Virginia. In: Reports of the Kettering Laboratory. University of Cincinnati, July 1953.
114. Homberger E, Reggiani G, Sambeth J, Wipf H. The Seveso accident: its nature, extent, and consequences. Ann Occup Hyg 1979;22:316-67.
115. Theiss AM, Frentzel-Beyme R, Link R. Mortality study of persons exposed to dioxin in a trichlorophenol-process accident that occurred in the BASF AG on November 17, 1953. Am J Ind Med 1982;3:179-89.
116. Cook RR, Townsend JC, Ott MG, Silverstein LG. Mortality experience of employees engaged in the manufacture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). J Occup Med 1980;22:530-2.
117. Bleiberg J, Wallen M, Brodkin R, Applebaum I. Industrially acquired porphyria. Arch Dermatol 1964;89:793-9.
118. Crow KD. Chloracne-an up to date assessment. Ann Occup Hyg 1978;21:297-8.
119. May G. Chloracne from the accidental production of tetrachlorodibenzodioxin. Br J Ind Med 1973; 30:276-83.
120. Mocarelli P, Marocchi A, Brambilla P, Mario-Gerthoux P, Young DS, Mantel N. Clinical laboratory manifestations of exposure to dioxin in children. A six-year study of the effects of an environmental disaster near Seveso, Italy. JAMA 1986;256:2687-95.
121. Goldman PJ. Critically acute chloracne caused by trichlorophenol decomposition products. Arbeitsmed Sozialmed Arbeitshyg 1972;7:12-8.
122. Poland AP, Smith D, Metter G, Possick P. A health survey of workers in a 2,4-D and 2,4,5-T plant with special attention to chloracne, porphyria cutanea tarda, and psychologic parameters. Arch Environ Health 1971;22:316-27.
123. Strik JJTWA. The occurrence of chronic hepatic porphyria in man caused by halogenated hydrocarbons. In: Strik JJTWA, Koeman JH, editors. Chemical porphyria in man. New York: Elsevier/North Holland, 1979:3-9.
124. Bogen G. Symptoms in Vietnam veterans exposed to Agent Orange. JAMA 1979;242: 2391.
125. Doss M, Sauer H, von Tiepermann R, Colombi AM. Development of chronic hepatic porphyria (porphyria cutanea tarda) with inherited uroporphyrinogen decarboxylase deficiency under exposure to dioxin. Int J Biochem 1984;16:369-73.
126. Pazderova J, Lukas E, Nemcova M, Spacilova M. Chronic poisoning by chlorinated hydrocarbons formed in the production of 2,4,5 sodium trichlorophenoxyacetate. Pracov Lek 1974;26:332-9.
127. Moses M, Prioleu OG. Cutaneous histologic findings in chemical workers with and without past exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin. J Am Acad Dermatol 1985;12:497.
128. Fitzgerald EF, Standfast SJ, Youngblood LG, Melius JM, Janerich DT. Assessing the health effects of potential exposure to PCBs, dioxins, and furans from electrical transformer fires: the Binghamton State Office Building medical surveillance program. Arch Environ Health 1986; 41:368-76.
129. Caputo R, Monti M, Ermacora E, Carminati G, Gelmetti C, Gianotti R, et al. Cutaneous manifestations of tetrachlorodibenzo-p-dioxin in children and adolescents. Follow-up 10 years after the Seveso, Italy, accident. J Am Acad Dermatol 1988;19:812-9.
130. Lathrop GD, Wolfe WH, Albanese RA, Moynahan PM. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides: baseline morbidity study results. Brooks Air Force Base, TX: US Air Force School of Aerospace Medicine, Aerospace Medical Division, 1984.
131. Kimbrough R. Morphology of lesions produced by the dioxins and related compounds. In: Human and environmental risks of chlorinated dioxins and related compounds. Tucker RE, Young AL, Gray AP, editors. New York: Plenum Press, 1983.
132. Greig J. Differences between skin and liver toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. Banbury Report 1984;18:391-7.
133. Puhvel SM, Sakamoto M, Ertl DC, Reisner RM. Hairless mice as models for chloracne: a study of cutaneous changes induced by topical application of established chloracnegens. Toxicol Appl Pharmacol 1982;64:492-503.
134. Kogan MD, Clapp RW. Mortality among Vietnam veterans in Massachusetts, 1972-1983. Boston: Massachusetts Office of Commissioner of Veterans Services, Agent Orange Program, Massachusetts Department of Public Health, Division of Health Statistics and Research, 1985.
135. Bond GG, McLaren EA, Lipps TE, Cook RR. Update of mortality among chemical workers with potential exposure to higher chlorinated dioxins. J Occup Med 1989;31: 121-3.
136. Fingerhut MA, Sweeney MH, Halperin WE, Schnorr TM. The epidemiology of populations exposed to dioxin. IARC Sci Publ 1991;108:31-50.
137. Thomas TL. Mortality among flavour and fragrance chemical plant workers in the United States. Br J Ind Med 1987;44:733-7.
138. Martin JV. Lipid abnormalities in workers exposed to dioxin. Br J Ind Med 1984; 41:254-6.
139. Pazderova-Vejlupkova J, Nemcova M, Pickova J, Jirasek L, Lukas E. The development and prognosis of chronic intoxication by tetrachlorodibenzo-p-dioxin in men. Arch Environ Health 1981;36:5-11.
140. Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, et al. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. Am J Ind Med 1984;5:161-82.
141. Carter CD, Kimbrough RD, Liddle JA, Cline RE, Zack MM Jr, Barthel WF, et al. Tetrachlorodibenzodioxin: an accidental poisoning episode in horse arenas. Science 1975;188:738-40.
142. Air Force Health Study. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides. Reproductive outcomes. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1992-0090. 1992. 602p.
143. Abbott BD, Birnbaum LS, Pratt RM. TCDD-induced hyperplasia of the ureteral epithelium produces hydronephrosis in murine fetuses. Teratology 1987;35:329-34.
144. Huuskonen H, Undila M, Pohjanvirta R, Tuomisto J. Developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the most TCDD-resistant and susceptible rat strains. Toxicol Appl Pharmacol 1994;124:174-80.
145. Giavini E, Prati M, Vismaro C. Rabbit teratology study: 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environ Res 1982;27:74-8.
146. Weber H, Harris MW, Haseman JK, Birnbaum LS. Teratogenic potency of TCDD, TCDF, and TCDD-TCDF combinations in C57BL/6N mice. Toxicol Lett 1985;26:159-67.
147. Couture-Haws L, Harris MW, Lockhart AC, Birnbaum LS. Evaluation of persistence of hydronephrosis induced in mice following in utero and/or lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 1991;107:402-12.
148. McConnell EE, Harris MW, Moore JA. The lack of effectiveness of activated charcoal and cholestyramine in reducing the body burden of polybrominated biphenyls. Drug Chem Toxicol 1980;3:277.
149. Gupta BN, McConnell EE, Moore JA, Haseman JK. Effects of a polybrominated biphenyl mixture in the rat and mouse. II. Lifetime study. Toxicol Appl Pharmacol 1983;68:18.
150. Giavini E, Prati M, Vismara C. Embryotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin administered to female rats before mating. Environ Res 1983;31:105-10.
151. Abbott BD, Morgan KS, Birnbaum LS, Pratt RM. TCDD alters the extracellular matrix and basal lamina of the fetal mouse kidney. Teratology 1987;35:335-44.
152. Christian BJ, Inhorn SL, Peterson RE. Relationship of the wasting syndrome to lethality in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 1986;82:239-55.
153. Moore JA, Gupta BN, Zinkl JG, et al. Postnatal effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Environ Health Perspect 1973;5:81-5.
154. Courtney KD. Mouse teratology studies with chlorodibenzo-p-dioxins. Bull Environ Contam Toxicol 1976;16:674-81.
155. U.S. Congress Office of Technology Assessment. Identifying and controlling immunotoxic substances - background paper. OTA-BP-BA-75. Washington, DC: U.S. Government Printing Office, 1991.
156. Tognoni G, Bonacocorsi A. Epidemiological problems with TCDD: a critical view. Drug Metab Rev 1982;13:447-69.
157. Reggiani G. Anatomy of a TCDD spill: the Seveso accident: hazard assessment of chemicals. Curr Dev 1983;2:269-342.
158. Webb KB, Evans RG, Knutsen AP, Roodman ST, Roberts DW, Schramm WF, Gibson BB, et al. Medical evaluation of subjects with known body levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Toxicol Environ Health 1989;28:183-93.
159. Evans RG, Webb KB, Knutsen AP, Roodman ST, Roberts DW, Bagby JR, Garret WA, Andrews JS. 1988. A medical follow-up of the health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Arch Environ Health 1988;43:273-8.
160. Vecchi A, Mantovani A, Sironi M, Luini W, Spreafico F, Garattini S. The effect of acute administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin on humoral antibody production and cell-mediated activities in mice. Arch Toxicol Suppl 1980;4:163-5.
161. Vecchi A, Sironi M, Canegrati MA, Recchia M, Garattini S. Immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with different susceptibility to induction of aryl hydrocarbon hydrolayse. Toxicol Appl Pharmacol 1983;68:434-41.
162. Holsapple MP, McCay JA, Barnes DW. Immunosuppression without liver induction by subchronic exposure to 2,7-dichlorodibenzo-p-dioxin in adult female B6C3F1 mice. Toxicol Appl Pharmacol 1986;83:445-55.
163. Kerkvliet NI, Brauner JA. Mechanisms of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD)-induced humoral immune suppression: evidence of a primary defect in T-cell regulation. Toxicol Appl Pharmacol 1987;87:18-31.
164. Faith RE, Luster MI, Moore JA. Chemical separation of helper cell function and delayed type hypersensitivity. Cell Immunol 1978;40:275-84.
165. Faith RE, Moore JA. Impairment of thymus-dependent immune functions by exposure of developing immune systems to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). J Toxicol Environ Health 1977;3:451-64.
166. U.S. Environmental Protection Agency. Health assessment document for polychlorinated dibenzo-p-dioxins. Cincinnati, OH: EPA, 1984.
167. Poland A. Biological mechanisms of dioxin action. Banbury Report 1984:18.
168. Poland A, Palen D, Glover E. Tumor promotion by TCDD in skin of HRS/J hairless mice. Nature 1982;300:271-3.
169. Pitot HC, Goldworthy T, Campbell AH, Poland A. Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogensis from diethylnitrosamine. Cancer Res 1980;40:3616-20.
170. Agency for Toxic Substances and Disease Registry. Dioxin toxicity. Am Fam Physician 1993;47:855-61.
171. Ott MG, Holder BB, Olson RD. A mortality analysis of employees engaged in the manufacture of 2,4,5-trichlorophenoxyacetic acid. J Occup Med 1980;22:47-50.
172. Zack J, Suskind R. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident. J Occup Med 1980;22:11-4.
173. Cook RR, Bond GG, Olson RA, Ott MG, Gondek MR. Evaluation of the mortality experience of workers exposed to the chlorinated dioxins. Chemosphere 1986;15:1769-76.
174. Smith AH, Fisher DO, Pearce NE, Chapmen CJ. Congenital defects and miscarriages among New Zealand 2,4,5-T sprayers. Arch Environ Health 1982;37:197-200.
175. Hardell L, Sandstrom A. Case control study: soft tissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. Br J Cancer 1979;39:711-7.
176. Axelson O, Sundell L, Anderson K, Edling C, Hogstedt C, Kling H. Herbicides exposure and tumor mortality: an updated epidemiologic investigation on Swedish railroad workers. Scand J Work Environ Health 1980;6:73-9.
177. Eriksson M, Hardell L, Berg NO, Moller T, Axelson O. Soft tissue sarcomas and exposure to chemical substances: a case-referent study. Br J Ind Med 1981;38:27-33.
178. Riihimaki V, Asp S, Pukkala E, Hernberg S. Mortality and cancer morbidity among chlorinated phenoxyacid applicators in Finland. Chemosphere 1983;12:779-84.
179. Balarajan R, Acheson ED. Soft tissue sarcomas in agriculture and forestry workers. J Epidemiol Community Health 1984;38:113-6.
180. Smith AH, Pearce NE, Fisher DO, Giles HJ, Teague CA, Howard JK. Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. J Natl Cancer Inst 1984;73:1111-7.
181. Lynge E. A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark. Br J Cancer 1985;52:259-70.
182. Vineis P, Terracini B, Ciccone G, Cignetti A, Colombo E, Donna A, et al. Phenoxy herbicides and soft-tissue sarcomas in female rice weeders-a population-based case-referent study. Scand J Work Environ Health 1986;13:9-17.
183. Hoar SK, Blair A, Holmes FF, Boysen CD, Robel RJ, Hoover R, et al. Agricultural herbicide use and risk of lymphoma and soft tissue sarcoma. JAMA 1986;256:1141-7.
184. Wiklund K, Holm L. Soft tissue sarcoma risk in Swedish agricultural and forestry workers. J Natl Cancer Inst 1986;76:229-34.
185. Wiklund K, Dich J, Holm LE. Risk of malignant lymphoma in Swedish pesticide appliers. Br J Cancer 1987;56:525-8.
186. Fingerhut MA, Halperin WE, Marlow DA, Piacttelli LA, Honchar PA, Sweeney MH, et al. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 1991;324:212-8.
187. Axelson O, Sundell L. Herbicide exposure, mortality and tumor incidence. An epidemiological investigation on Swedish railroad workers. Scand J Work Environ Health 1974;6:73-9.
188. Fett MJ, Dunn M, Adena M. The mortality study. Part 2. A retrospective study of mortality among Australian national servicemen of the Vietnam conflict era. Canberra: AGPS, 1984.
189. Bond GG, Wetterstroem NH, Roush GJ, McLaren EA, Lipps TE, Cook RR. Cause specific mortality among employees engaged in the manufacture, formulation, or packaging of 2,4-dichlorophenoxyacetic acid and related salts. Br J Ind Med 1988;45:98-105.
190. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 1991;338:959-64.
191. Zack JA, Gaffey WR. A mortality study of workers employed at the Monsanto Company in Nitro, West Virginia. Environ Sci Res 1983;26:575-91.
192. Fingerhut M, Halperin W, Marlow D, Piacitelli L, Honchar P, Sweeney M, et al. Mortality among US workers employed in the production of chemicals contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). NIOSH Final Report PB91125971. Springfield, VA: National Technical Information Service, 1990.
193. Bertazzi PA, Pesatori AC, Consonni D, Tironi A, Landi MT, Zocchetti C. Cancer incidence in a population accidentally exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. Epidemiology 1993;4:398-406.
194. Zoeber A, Messerer P, Huber P. Thirty-four year mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. Int Arch Occup Environ Health 1990;62: 139-51.
195. Kogevinas M, Saracci R, Winkelmann R, Johnson ES, Bertazzi PA, Bueno de Mesquita BH, et al. Cancer incidence and mortality in women occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins. Cancer Causes Control 1993;4:547-53.
196. Erickson JD, Mulinare J, McClain PW, Fitch TG, James LM, McClearn AB, et al. Vietnam veterans' risks for fathering babies with birth defects. JAMA 1984;252: 903-12.
197. May G. Tetrachlorodibenzodioxin: a survey of subjects ten years after exposure. Br J Ind Med 1982;39:128-35.
198. Evart P. Royal Commission on the use and effects of chemical agents on Australian personnel in Vietnam: final report, Vol. 1-9. Canberra, Australia: AGPS, 1985.
199. Ott MG, Olson RA, Cook RR, Bond GG. Cohort mortality study of chemical workers with potential exposure to the higher chlorinated dioxins. J Occup Med 1987;29:422-9.
200. Hardell L, Bengtsson NO, Jonsson U, Ericksson S, Larsson LG. Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria-an epidemiological investigation. Br J Cancer 1984;50:389-94.
201. Thiess AM, Frentzel-Beyme R, Link R. Mortality study of persons exposed to dioxin in a trichlorophenol-process accident that occurred in the BASF/AG on November 17, 1953. Am J Ind Med 1982;3:179-89.
202. Hardell L. Relation of soft tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chlorophenols and other agents. Scand J Work Environ Health 1981;7:119-30.
203. Van DD. Herbicides as a possible cause of liver cancer. In: Westing AH, editor. Herbicides in war, the long-term ecological and human consequences. London: Taylor and Francis, 1984:119-21.
204. Hardell L, Johansson B, Axelson O. Epidemiological study of nasal and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. Am J Ind Med 1982;3:247-57.
205. Barthel E. Increased risk of lung cancer in pesticide-exposed male agricultural workers. J Toxicol Environ Health 1981;8:1027-40.
206. Saracci R, Kogevinas M, Bertazzi PA, Bueno De Mesquita BH, Coggon D, Green LM, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 1991;338:1027-32.
207. Greenwald P, Kovasznay B, Collins DN, Therriault T. Sarcomas of soft tissue after Vietnam service. J Natl Cancer Inst 1984;73:1107-9.
208. Lawrence CE, Reilly AA, Quickenton P, Greenwald P, Page WF, Kuntz AJ. Mortality patterns of New York State Vietnam veterans. Am J Public Health 1985;75:277-9.
209. Aust SD. On the mechanism of anorexia and toxicity of TCDD and related compounds. Banbury Report. 1984;18:309-19.
210. Kang HK, Weatherbee L, Breslin PP, Lee Y, Shepard BM. Soft tissue sarcoma and military service in Vietnam: a case comparison group analysis of hospital patients. J Occup Med 1986;28:1215-8.
211. Smith AH, Fisher DO, Giles HJ, Pearce N. The New Zealand soft tissue sarcoma case-control study: interview findings concerning phenoxyacetic acid exposure. Chemosphere 1983;12:565-71.
212. Woods JS, Polissar L, Severson RK, Heuser LS, Kulander BG. Soft tissue sarcoma and non-Hodgkin's lymphoma in relation to phenoxy herbicide and chlorinated phenol exposure in western Washington. J Natl Cancer Inst 1987;78:899-910.
213. Vineis P, Terracini B, Ciccone G, Cignetti A, Colombo E, Donna A, et al. Phenoxy herbicides and soft tissue sarcomas in female rice weeders: a population-based case-control study. Scand J Work Environ Health 1987;13:9-17.
214. Kang H, Enziger F, Breslin P, Feil M, Lee Y, Shepard B. Soft tissue sarcoma and military service in Vietnam: a case-control study. JNCI 1987;79:693-9.
215. Milham S Jr. Herbicides, occupation, and cancer. Lancet 1982;1:1464-5.
216. Hardell L, Eriksson M. The association between soft tissue sarcomas and exposure to phenoxyacetic acids, a new case referent study. Cancer 1988;62:652-6.
217. Greenwald P, Kovasznay B, Collins DN, Therriault G. Sarcomas of soft tissues after Vietnam service. JNCI 1984;73:1107-9.
218. Hardell L. Malignant mesenchymal tumors and exposure to phenoxyacetic acids-a clinical observation. Lakartidningen 1977;74:2753-4.
219. Cook RR. Dioxin, chloracne and soft tissue sarcoma. Lancet 1981;1:618-9.
220. Honchar P, Halperin W. 2,3,5-T, trichlorophenol, and soft tissue sarcoma. Lancet 1981;1:268-9.
221. Moses M, Selikoff IJ. Soft-tissue sarcomas, phenoxy herbicides and chlorinated phenols. Lancet 1981;1:1370.
222. Angeli F. Study of cancer incidence at Seveso. Presented at the 6th Meeting of the International Steering Committee. Ufficio Speciale per Seveso, Bruzzano, Milano, Italy, 1984.
223. Puntoni R, Merlo F, Fini A, Meazza L, Santi L. Soft tissue sarcomas in Seveso [letter]. Lancet 1986;2:525.
224. Bahn AK, Rosenwaike I, Hermann N, Grover P, Stellman J, O'Leary K. Melanoma after exposure to PCBs [letter]. N Engl J Med 1976; 295:450.
225. Bullman TA, Watanabe KK, Kang HK. Risk of testicular cancer associated with surrogate measures of Agent Orange exposure among Vietnam veterans on the Agent Orange Registry. Ann Epidemiol 1994;4:11-6.
226. Hardell L, Eriksson M, Lenner P, Lundgren E. Malignant lymphoma and exposure to chemicals, especially organic solvents, chlorophenols, and phenoxy acids: a case-control study. Br J Cancer 1981;43:169-76.
227. Pearce NE, Smith AH, Howard JK, Sheppard RA, Giles HJ, Teague CA. Non-Hodgkin's lymphoma and exposure to phenoxy herbicides, chlorophenols, fencing work, and meat works employment: a case-control study. Br J Ind Med 1986;43:75-83.
228. Eriksson M, Hardell L, Malker H, Weiner J. Malignant lymphoproliferative diseases in occupations with potential exposure to phenoxyacetic acids or dioxins: a register-based study. Am J Ind Med 1992;22:305-12.
229. Cantor KP. Farming and mortality from non-Hodgkin's lymphoma: a case-control study. Int J Cancer 1982;29:239-47.
230. Pesatori AC, Consonni D, Tironi A, Zocchetti C, Fini A, Bertazzi PA. Cancer in a young population in a dioxin-contaminated area. Int J Epidemiol 1993;22:1010-3.
231. Wiklund K, Dich J, Holm LE. Soft-tissue sarcoma risk in Swedish licensed pesticide applicators. J Occup Med 1988;30:801-4.
232. Hoar Zahm S, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, et al. A case-control study of non-Hodgkin's lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in Eastern Nebraska. Epidemiology 1990;1:349-56.
233. Hardell L, Bengtsson NO. Epidemiologic study of socioeconomic factors and clinical findings in Hodgkin's disease and reanalyses of previous data regarding chemical exposure. Br J Cancer 1983;48:217-25.
234. Grufferman S, Delzell E. Epidemiology of Hodgkin's disease. Epidemiol Rev 1984;6:76-106.
235. Hardell L, Bengtsson NO. Epidemiological study of socioeconomic factors and clinical findings in Hodgkin's disease, and reanalysis of previous data regarding chemical exposure. Br J Cancer 1984;48:217-25.
236. Persson B, Dahlander A, Fredriksson M, Brage NH, Ohlson CG, Axelson O. Malignant lymphoma and occupational exposures. Br J Ind Med 1989;46:516-20.
237. Ericksson M, Hardell L, Adami HO. Exposure to dioxins as a risk factor for soft tissue sarcoma: a population-based case-control-study. J Natl Cancer Inst 1990;82:486-90.
238. Blair A, Malker H, Cantor KP, Burmeister L, Wiklund K. Cancer among farmers. A review. Scand J Work Environ Health 1985;11:397-407.
239. Wigle DT, Semenciw RM, Wilkins K, Riedel D, Ritter L, Morrison HI, Mao Y. Mortality study of Canadian male farm operators: non-Hodgkin's lymphoma mortality and agricultural practices in Saskatchewan. J Natl Cancer Inst 1990;82:575-82.
240. Pearce NE Sheppard RA, Smith AH, Teague CA. Non-Hodgkin's lymphoma and farming: an expanded case-control study. Int J Cancer 1987;39:155-61.
241. Wiklund K. Swedish agricultural workers: a group with a decreased risk of cancer. Cancer 1983;51:566-8.
242. Breslin P, Kang H, Lee Y, Burt V, Shepard BM. Proportionate mortality study of U.S. Army and U.S. Marine Corps veterans of the Vietnam War. J Occup Med 1988;30:412-9.
243. US Environmental Protection Agency. Health assessment document for polychlorinated dibenzo-p-dioxins. Washington, DC: US Environmental Protection Agency, Office of Health and Environmental Assessment, 1985. EPA Report no. 600/8-84/014.
244. Huff JE, Salmon AG, Hooper NK, Zeise L. Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzeno-p-dioxins. Cell Biol Toxicol 1991;7:67-94.
245. Zeise L, Huff JE, Salmon AG, Hooper NK. Human risks from 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins. In: Advances in modern environmental toxicology, v. 17. Princeton, NJ: Princeton Scientific Publishing Co., Inc. 293-342.
246. National Toxicology Program. Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Osborne-Mendel rats and B6C3F1 mice. Washington, DC: National Toxicology Program, 1982. Publication no. (NTP) 80-31.
247. Toth K, Somfai-Relle S, Sugar J, Bence J. Carcinogenicity testing of herbicide 2,4,5-trichlorophenoxyethanol containing dioxin and of pure dioxin in Swiss mice. Nature 1979; 278:548-9.
248. Rao MS, Subbarao V, Prasad JD, Scarpelli DG. Carcinogenicity of 2, 3,7,8-tetrachlorodibenzo-p-dioxin in the Syrian golden hamster. Carcinogenesis 1988;9:1677-9.
249. Safe SH. Comparative toxicology and mechanism of action of polychlorinated dibenzo-p-dioxins and dibenzofurans. Annual Review of Pharmacology and Toxicology 1986;26:371-99.
250. Hay A. The chemical scythe. New York: Plenum Press, 1982.
251. Nebert DW, Jensen NM. The Ah locus: genetic regulation of the metabolism of carcinogens, drugs, and other environmental chemical by cytochrome P-450-mediated monoxygenases. CRC Crit Rev Biochem 1979;6:401-37.
252. Kociba R. Evaluation of the carcinogenic and mutagenic potential of 2,3,7,8-TCDD and other chlorinated dioxins. In: Poland A, Kimbrough RD, eds. Biological mechanisms of dioxin action. Banbury Report 1984;18:73-84.
253. Kimbrough RD. Consumption of fish: benefits and perceived risk. J Toxicol Environ Health 1991;33:81-91.

• Home
• Privacy Policy
• Disclaimer
• Accessibility
• e-Government
• FOIA
• Contact Us