An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

BACKGROUND: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. PATIENTS AND METHODS: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. RESULTS: Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, -34.6%; 1400 mg, -41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response. CONCLUSIONS: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT01046266 (ClinicalTrials.gov).

Cancer incidence in the wastewater treatment plant of a large chemical company.

OBJECTIVES: To evaluate cancer incidence among employees assigned to BASF's wastewater treatment plant. METHODS: We conducted a retrospective cohort study including 477 male employees who had ever worked in the facility for at least 1 year since the start of operations in 1974. Cancers were identified by review of occupational medical records and a standardized questionnaire completed by the participants or their next of kin. Confirmation through hospital records was sought for all reported cases after obtaining informed consent. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were computed using comparison data provided by the Saarland Cancer Registry. Further comparisons were made between three different subgroups of employees, working in maintenance, wastewater processing, and sewage sludge treatment. RESULTS: A total of 50 cancers were observed (SIR 1.14, CI 0.85-1.51). Colorectal (1.14, 0.42-2.48), bronchial (1.40, 0.67-2.57) and prostate (1.15, 0.42-2.50) were the most frequently observed cancers. Five cases of bladder cancer were found in the total cohort (1.75, 0.57-4.09), with four of them occurring in the sewage sludge treatment area (6.82, 1.86-17.46). Allowing for a 10-year lag did not significantly change the results. CONCLUSIONS: The overall cancer experience among employees of the wastewater treatment plant was similar to that of the corresponding general population. The finding of an excess risk for bladder cancer in one subgroup of workers was unexpected with regard to the available literature. There is no straightforward explanation for this finding, and it may be due to chance. An extended follow-up of this cohort will take place after 5 years. Annual bladder cancer screening is offered to active and retired employees from this plant for the time being. The current working conditions and work practices have been re-assessed by occupational hygienists and deemed to be safe.

Progress and prospects: gene therapy clinical trials (part 1).

Over the last two decades gene therapy has moved from preclinical to clinical studies for many diseases ranging from single gene disorders such as cystic fibrosis and Duchenne muscular dystrophy, to more complex diseases such as cancer and cardiovascular disorders. Gene therapy for severe combined immunodeficiency (SCID) is the most significant success story to date, but progress in many other areas has been significant. We asked 20 leaders in the field succinctly to summarize and comment on clinical gene therapy research in their respective areas of expertise and these are published in two parts in the Progress and Prospect series.

Gene therapy of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder which results from absence or malfunction of the respiratory burst oxidase normally expressed in neutrophils and other phagocytic leukocytes. Two-thirds of the patients are males hemizygous for mutations in the X-linked gene coding for gp91-phox. As a therapeutic approach towards the X-linked form of CGD bicistronic retroviral vectors containing the gp91-phox gene and a selectable marker gene were constructed. The ability of these vectors to restore NADPH oxidase activity was tested in a human myeloid leukemic cell line that is defective in superoxide production, as well as in primary CD34+ cells obtained from X-CGD patients. Under optimal conditions 80% of the CD34+ cells derived from bone marrow of one X-CGD patient were transduced. The level of superoxide production, in phagocytes derived from transduced cells was 68.9% of normal levels. Considering that low levels of superoxide generating activity are sufficient for normal host defense, the present experiments provide the basis for the development of a gene replacement therapy for the X-linked form of CGD.

Respiratory health surveillance in a toluene di-isocyanate production unit, 1967-97: clinical observations and lung function analyses.

OBJECTIVES: To characterise irritant and allergic airway responses and assess changes in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) relative to exposure to toluene di-isocyanate (TDI). METHODS: Employees (n = 313) ever assigned to a TDI production unit for > or = 3 months (1967-92) were identified from personnel records along with 158 frequency matched referents without known exposure to TDI. Reports made during visits to the occupational clinic of incidents related to exposure to TDI and annual periodic examination results (questionnaire, physical findings, and spirometry) were abstracted and assessed relative to industrial hygiene estimates of exposure to TDI. RESULTS: Mean 8 hour time weighted average estimates of TDI concentrations ranged from 9.9 ppb in jobs with potentially high exposure during the early years of plant operations to 0.5 ppb in jobs with potentially low exposure in more recent years. The corresponding rates of visits to the clinic due to incidents of exposure to TDI (including both irritant and allergic airway responses) declined from 20.5 to 1.0 visits per 100 years of employment at the unit. The annual incidence of asthma induced by TDI declined from 1.8% before 1980 to 0.7% afterwards. Neither cross sectional nor longitudinal analyses of FVC and FEV1 showed significant dose-response findings relative to exposure to TDI across the total exposed population. Among cases of occupational asthma there was an apparent initial decline in FEV1 within 2 years of first reporting symptoms, but not an accelerated rate of decline in follow up tests from 4-30 years after induction of asthma. CONCLUSIONS: Occurrences of both asthma induced by TDI and irritant airway responses due to exposure to TDI were found in this cohort, but there was no relation between cumulative exposure to TDI and irreversible airflow obstruction as assessed by spirometry.

[Leptospirosis after a staff outing]. / Leptospirose-Erkrankungen nach einem Betriebsausflug.

HISTORY AND CLINICAL FINDINGS: Three male colleagues aged between 34 and 38 years were admitted at the same time to three different Rhein-Main area Hospitals. They presented with a variety of symptoms, including high fever (39.0 to 40.0 degrees C), chills, headache with meningismus or facial paralysis, mild hepatitis and renal involvement. About 18 days before they had been together on a boat rafting tour when the boat capsized when they had fallen into a river in high flood. INVESTIGATIONS: Laboratory tests showed elevated inflammatory parameters, signs of a mild hepatitis and renal involvement. All patients had leptospirosis antibodies, detected by immunofluorescence test. In two cases there was evidence of antibodies against Leptospira interrogans serovar bataviae in the microscopic agglutination test (MAT). TREATMENT AND COURSE: The history and clinical presentation indicated leptospirosis in all patients, in two cases confirmed by laboratory findings. Following therapy with doxycycline or ceftriaxone, symptoms resolved quickly and permanently. CONCLUSION: Leptospires of serogroup Bataviae is a known pathogen of anicteric non-Weil leptospirosis. The symptoms are non-specific and, moreover, in some cases the laboratory tests are negative, so that clinical diagnosis remains crucial. Typically there is a history of contact with contaminated water or urine. In our cases striking neurotropism was observed, which may be characteristic for this serovar.

Specific Helicobacter pylori antigens unable to distinguish nonucler dyspepsia or peptic ulcer cases from asymptomatic seropositive controls: a nested case-control study in employees of a large company.

We investigated in a large industrial population the antibody response to specific H. pylori antigens (CagA and seven others) in relation to peptic ulcer and nonulcer dyspepsia (NUD). The two groups consisted of 37 and 39 employees, respectively, with endoscopically proven peptic ulcer and NUD. Age- and gender-matched controls were H. pylori seropositive employees without abdominal complaints or history of ulcer disease. IgG antibodies against CagA and other antigens were analyzed by western immunoblot. Relative percentages of CagA-positive individuals were 89 and 76% for ulcer cases and their controls (P = 0.22) and 77% and 74% for NUD cases and their controls. The corresponding percentages of VacA-positive individuals were 87 and 76% for ulcer cases and controls and 64% and 77% for NUD cases and controls, respectively. Analysis of other H. pylori-specific antigens was not particularly helpful in discriminating between symptomatic and asymptomatic seropositive individuals for either disease group. In conclusion, assessment of IgG response against specific H. pylori antigens was not predictive of peptic ulcer or NUD case status in this active employee population and would not appear to be useful in routine clinical practice.

Diisocyanates in polyurethane plastics applications.

Diisocyanates are a group of low molecular weight aromatic and aliphatic compounds, widely used in the manufacture of polyurethanes. The most commonly used of these compounds are toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), and hexamethylene diisocyanate (HDI). This article presents a brief summary of the use of diisocyanates in the manufacture of polyurethane products and a review of the epidemiology, medical surveillance, and clinical diagnosis of respiratory and dermal effects of diisocyanates, with emphasis on diisocyanate asthma.

Correction of respiratory burst activity in X-linked chronic granulomatous cells to therapeutically relevant levels after gene transfer into bone marrow CD34+ cells.

Chronic granulomatous disease (CGD) is a disorder of the lymphohematopoietic system, whereby phagocytes of affected patients are unable to kill microorganisms. CGD is caused by a functional defect in the phagocytic nicotinamide adenine dinucleotide phosphatase (NADPH) oxidase (phox) enzyme complex, leading to a lack of microbicidal metabolites. As a therapeutic approach toward the predominant X-linked form of CGD, we have developed a bicistronic retroviral vector containing the coding sequences of gp91-phox and a cytoplasmically truncated version of the human low-affinity receptor for nerve growth factor (deltaLNGFR). Full reconstitution of superoxide-generating activity was achieved with this vector in a gp91-phox-deficient cell line. Using an optimized gene transfer protocol, up to 85% of the CD34+ cells obtained from the bone marrow of X-CGD patients were transduced. CD15+ cells differentiated in vitro from transduced X-CGD CD34+ cells showed correction of NADPH oxidase activity to 45-52% of normal levels whereas deltaLNGFR expression was found in 40-67% of the CD15+ cells. Moreover, immunoblots prepared from extracts of transduced CD15+ cells revealed gp91-phox protein levels similar to those found in neutrophils derived from normal CD34+ cells. Taking into consideration that superoxide production in only 5 to 10% of wild-type neutrophils is sufficient to protect X-CGD heterozygotes from serious infections, the results achieved in this study shows that for X-CGD patients a curative approach based on the genetic modification of hematopoietic stem/progenitor cells is feasible.

Helicobacter pylori infection: prevalence and clinical relevance in a large company.

Although gastrointestinal (GI) illnesses account for considerable sick absenteeism, there have been few workplace studies of GI disorders. We determined the prevalence of Helicobacter pylori infection by serology and assessed its relation to upper GI tract complaints, personal ulcer history, and family history of stomach cancer in 6,143 employees (mean age, 40.4 years) at BASF's main chemical production facilities in Ludwigshafen, Germany. Employees were recruited during occupational health clinic visits (n = 4,488) and through broad communications efforts (n = 1,655). Participation among clinic attendees was 66%, and this recruitment method was particularly effective in reaching shift employees. Positive immunoglobulin G (IgG) serology (38.2%), ulcers (4.9%), nonulcer dyspepsia (20.4%), and a family history of stomach cancer (6.1%) were common occurrences in this work setting. Further diagnostic evaluation and eradication therapy was recommended for 795 employees (12.9%), based on a combination of positive serology and either upper GI tract complaints or family stomach cancer history, and has been completed for 541 employees. A weak but consistent association was seen between positive serology and cigarette smoking, and shift work was found to be associated with positive serology, but not with ulcer or nonulcer dyspepsia occurrence.

BASF studies: epidemiological and clinical investigations on dioxin-exposed chemical workers.

First in 1953 and again later in 1988, BASF Aktiengesellschaft, Ludwigshafen, Germany, faced production-related dioxin contamination problems. In both situations, the immediate actions were efforts to limit the potential for employee exposure. In 1953, after a reactor accident, the production of trichlorophenol was stopped and extensive clean-up and demolition work was undertaken. In 1988, major technical improvements were made to an extrusion blending process and the flame retardants were changed to substances that chemically should not be dioxin precursors. The health experience of the potentially exposed populations has been followed extensively in both situations. Five recent epidemiological investigations: a long-term mortality follow-up, a morbidity study, a clinical laboratory study, and a chromosome study of persons from the 1953 accident cohort, as well as immunological studies of employees assigned to the extrusion operations, are discussed. In addition, considerable dioxin biomonitoring data from blood lipids for both populations are summarized.

Morbidity study of extruder personnel with potential exposure to brominated dioxins and furans. II. Results of clinical laboratory studies.

OBJECTIVE: To test whether dioxins affect liver and thyroid function, lipid metabolism and glucose or immunological variables, in workers exposed to brominated dioxins and furans. METHODS: 34 male production employees (29 were extruder operators) and eight technical support personnel were studied, all of whom were potentially exposed to polybrominated dibenzo-p-dioxins (PBDDs) and furans (PBDFs) during production of resins containing polybrominated diphenyl ethers (PBDEs). Controls were from a similar resin producing plant that did not use PBDEs. Blood samples were analysed for tetra, penta, and hexabrominated congeners, but 2,3,7,8-TBDD was the only exposure measure used in the regression analyses. Seven liver function indicators, five measures of blood lipids and glucose, four haematology and blood coagulation measures, and three measures of thyroid function were examined. RESULTS: None of the variables was statistically related to concentration of 2,3,7,8-TBDD in the regression analyses. Cigarette smoking was related to several outcomes at the 0.05 level: aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase (GLDH), erythrocyte sedimentation rate, and white blood cell count. Body mass index was also related to alanine aminotransferase, gamma-glutamyltranspeptidase, cholinesterase, GLDH, cholesterol, triglycerides, high density lipoprotein, low density lipoprotein, and glucose concentrations. No definitive associations between liver, blood lipid, thyroid, or immunological variables and exposure to brominated dioxins or blood lipid concentration of 2,3,7,8-TBDD were found. CONCLUSIONS: The study population was small and hence the findings must be interpreted with caution. Nevertheless, these results provide a base for interpreting the results of clinical studies in similarly exposed populations.

Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident.

OBJECTIVE: To evaluate the long term health consequences of past occupational exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). METHODS: Cancer incidence and cause specific mortality were examined up to and including 1992 in a group of 243 men with external comparisons and internal dose-response analyses. Model based estimates of TCDD dose (expressed in micrograms/kg body weight) were developed for all cohort members with an approach that incorporated detailed accounts of each employee's work activities, analyses of TCDD in blood lipid of 138 employees, and internally derived estimates of elimination rates of TCDD. RESULTS: The estimated dose of TCDD for 135 men was > or = 0.1 microgram/kg body weight and for 69 men > or = 1 microgram/kg body weight. Increased cancer risk ratios were found with higher doses of TCDD and longer interval since first exposure for all sites combined and digestive and respiratory cancers in particular. Within the high dose group (> or = 1 microgram/kg body weight), total cancer mortality was increased > or = 20 years after first exposure (13 cases, standardised mortality ratio (SMR) 1.97, 95% confidence interval (95% CI) 1.05-3.36) as was respiratory cancer (six cases, SMR 3.06; 95% CI 1.12-6.66). Among current cigarette smokers, 12 cancer deaths occurred in the high dose group (SMR 3.42, 95% CI 1.77-5.97) compared with seven deaths at lower doses of TCDD (SMR 1.29, 95% CI 0.52-2.66). Regression analyses based on the Cox's proportional hazards model provided further evidence of a relation between cumulative dose of TCDD and occurrence of both overall and digestive cancer. No evidence of an effect of TCDD on overall mortality or deaths due to circulatory disease was found and no cases of non-Hodgkin's lymphoma or soft tissue sarcoma have been found to date. CONCLUSIONS: Our findings are consistent with a carcinogenic effect induced by TCDD at doses > or = 1 microgram/kg body weight. With such a small cohort, the risk estimates are not very stable and could be affected by selection and confounding.

Mortality experience among Louisiana chemical manufacturing employees, 1957-1992.

A cohort mortality study was undertaken of persons ever employed at BASF's Geismar, Louisiana chemical manufacturing facilities for 3+ months prior to 1992. The 1,870 men and 263 women employees were traced through 1992 (99% follow-up) using employment and pension records, National Death Index searches, social security record matching, and credit bureau checks. Death certificates were obtained and coded for 92% of the 128 decedents. Overall and total cancer deaths among short-term ( < 10 years of site employment) and long-term hourly and salaried employees were fewer than expected based on comparisons to US general population death rates. Deaths due to external causes were higher than expected among short-term hourly employees (23 observed compared to 16 expected deaths). Among all employees, three accidental deaths occurred at work, the most recent in 1981. Four deaths each, due to urinary and brain cancers, exceeded expectation; however, there was no pattern of job assignments suggesting a work-related etiology for these occurrences.

Peripheral natural killer cell activity and intraperitoneal soluble p55 tumor necrosis factor receptor in patients with malignant ascites: two possible indicators for response to intraperitoneal combined tumor necrosis factor alpha and interferon gamma treatment.

Tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) are important immunomodulators. They are capable of acting in a synergistic manner on tumor cells in vitro and in vivo. In a clinical phase I study 13 patients with malignant ascites due to abdominal spread of different primary tumors received intraperitoneally (i.p.) TNFalpha and IFNgamma once weekly over 3-8 weeks in order to evaluate the effect of locoregionally administered TNFalpha/IFNgamma on ascites formation. Therefore some peripheral and local immunological functional parameters of peripheral blood and malignant ascites were investigated. Mononuclear lymphocytes and natural killer (NK) cell activity of peripheral blood and ascites, TNF-inhibitory activity, soluble p55 and p75 TNF receptors, and prostaglandin E2 values in ascites were measured immediately before and 24 h after each TNFalpha/IFNgamma infusion. Peripheral mononuclear lymphocytes and NK activity decreased significantly 24 h after i.p. TNFalpha/IFNgamma application. However, over the entire treatment schedule, peripheral NK activity in all responders showed a continuous increase, when compared to pre TNFalpha/IFNgamma treatment levels. In contrast, NK activity in non-responders constantly decreased. In contrast to non-responders, TNF-inhibitory activity and soluble p55 TNF receptor levels, determined in ascites, decreased in responders. Taken together, our findings suggest, that successful locoregional i.p. TNFalpha/IFNgamma therapy induces systemic immunological reactions possibly after saturation of soluble p55 TNF receptors in ascites, which leads to an increase of peripheral NK activity.

Investigation of a cluster of ten cases of Hodgkin's disease in an occupational setting.

The objective of this study was to identify occupational exposures that might be etiologically linked to an unusual cluster of ten cases of Hodgkin's disease. The cases were identified within the active workforce of a large chemical manufacturing firm over a 23-year period by the medical director of the facilities. Based on comparison with regional cancer incidence rates, the standardized incidence ratio for Hodgkin's disease was 497 (95% confidence interval: 238-915) for the period from the construction of the facilities in 1966 through early 1992. A nested case-control study was undertaken with 200 controls selected according to case-cohort sampling. Simultaneously, efforts were initiated to confirm and characterize each case more fully. Occupational exposures were identified and categorized using process, work history, medical record, and industrial hygiene data. Tissue slides were available for eight cases and a second review confirmed the diagnosis of Hodgkin's disease. For one case, a final diagnosis of large-cell anaplastic lymphoma was determined after histology review. Among 214 different chemical agents studied, eight were identified to which three or more of the cases had been exposed prior to the date of their initial diagnosis. Exposure odds ratios were statistically elevated for five of these agents; dose-response evaluations for two of the agents, ethylene oxide and benzene, failed to provide additional support for a causal relationship. In conclusion, although several statistical associations were identified, no substance emerged as a likely candidate for explaining the observed Hodgkin's disease cluster.

Study of morbidity of personnel with potential exposure to vinclozolin.

OBJECTIVES: To examine internal exposure and targeted health outcomes of employees exposed to 3-(3,5-dichlorophenyl)-5-methyl-5-vinyl-1,3-oxazolidine-2,4-dione; chemical abstracts service (CAS) number: 50471-44-8 (vinclozolin). METHODS: A cross sectional study of 67 men exposed to vinclozolin for one to 13 years during synthesis and formulation operations and 52 controls. Biomonitoring was based on determination of urinary metabolites that contained a 3,5-dichloroaniline (3,5-DCA) moiety. Targeted health endpoints were the same as in previous subchronic and chronic animal studies--namely, reversible changes in the concentrations of hormones of the adrenocorticotrophic and gonadotrophic feedback systems, signs of liver injury, haemolytic anaemia, cataract formation (uniquely in rats), and hormonally induced hyperplasia and tumours at high doses. The clinical investigation consisted of a medical and occupational history questionnaire, physical examination, laboratory determinations (including testosterone, LH, and FSH measurements), ultrasonography of the liver and prostate, a detailed eye examination, and routine spirometry. RESULTS: The mean 3,5-DCA concentration for two thirds of the study group exceeded an equivalent of the vinclozolin acceptable daily intake (ADI) used for consumer regulatory purposes. Even the highest concentrations were, however, at least 10 times below the no observable adverse effect level (NOAEL) based on animal studies. Analysis of physical examination and laboratory data provided no evidence of hormonal responses induced by vinclozolin. Furthermore, no evidence of liver injury, prostate changes, cataract formation, or haemolytic anaemia was found. CONCLUSION: There was no evidence of any health effects induced by vinclozolin among employees with potential long term exposure. In particular, no antiandrogenic effects were found.

Laboratory results for selected target organs in 138 individuals occupationally exposed to TCDD.

Blood specimens for dioxin congener analysis and clinical laboratory studies were recently obtained for 138 employees who had been potentially exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) following a 1953 trichlorophenol autoclave accident. Results for 34 clinical tests were regressed on three exposure measures (current TCDD concentration, log TCDD concentration back-calculated to the time of exposure, and chloracne status). Age, smoking status and body-mass-index were included as additional explanatory factors in the analyses. Positive associations were found between each of the exposure measures and both serum thyroxine (T4) and thyroxine binding globulin (TBG). Additional exposure-response associations were detected relative to several immune system parameters, erythrocyte sedimentation rate, platelet count and serum alkaline phosphatase. These data will be specifically helpful in interpreting the results of additional morbidity and mortality studies conducted within the same target population.

Morbidity follow up study of BASF employees exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical reactor incident.

OBJECTIVE: The aim was to examine the long term morbidity experience of men exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). METHODS: A retrospective cohort morbidity study of 158 men first exposed to TCDD between 17 November 1953 and 16 November 1954 subdivided by chloracne state and back calculated TCDD blood lipid concentration, and 161 referents. Cause specific illness absence and admissions to hospital were examined between 1953 and 1989. RESULTS: On an ever or never basis, thyroid disease and appendicitis were diagnosed more often in the study group; these diseases were not differentially distributed by chloracne state, but were increased in the high TCDD subgroup. An 18% increase in total illness episodes was also seen (p = 0.002); illness rates increased with severity of chloracne and higher TCDD concentration within the chloracne subgroup. There were increases in infectious and parasitic diseases (primarily ill defined intestinal infections), disorders of the peripheral nervous system and sense organs, upper respiratory tract infections, and other skin diseases. Several of these increases correlated with chloracne state and infections disease episodes increased with higher TCDD concentration as well. Occurrences of mental disorders correlated with severity of chloracne, but not TCDD concentration. Benign and unspecified neoplasms were marginally increased in the severe chloracne and high TCDD subgroups. Chronic liver disease was marginally increased in the high TCDD subgroup. Findings relative to occurrence of ulcers, chronic lung disease, and kidney and metabolic disorders were unremarkable. DISCUSSION: For various conditions, increased illness episodes were seen among TCDD exposed employees compared with referents and were associated with either or both chloracne severity and back calculated TCDD concentration. The results are derived from insurance data; hence, it is possible that heightened awareness and personal health concerns led to greater utilisation of medical services in the exposed group. The findings based on TCDD concentration should be less subject to this potential bias.