DDT and related compounds and risk of pancreatic cancer.

BACKGROUND: A cohort mortality study among 5886 chemical manufacturing workers was completed in 1987 and showed increased mortality due to pancreatic cancer. PURPOSE: We conducted a nested case-control study of pancreatic cancer among these chemical manufacturing workers to identify risk factors for this disease. METHODS: Twenty-eight verified cases of pancreatic cancer and 112 matched controls were studied. Next of kin of each subject were interviewed to determine lifestyle factors, including tobacco, alcohol, and coffee consumption. Written work records and interviews with co-workers were used to determine chemical exposures at the plant under study. RESULTS: DDT was associated with pancreatic cancer (risk ratio [RR] for ever exposed compared with never exposed = 4.8; 95% confidence interval = 1.3-17.6). Among subjects who had a mean exposure to DDT of 47 months, the risk was 7.4 times that among subjects with no exposure. Two DDT derivatives, Ethylan and DDD, were additionally associated with pancreatic cancer (RR = 5.0 and 4.3, respectively); exposures to these two chemicals were correlated, and it was not possible to determine whether each acted independently of the other. Smoking was identified as an independent risk factor, but controlling for smoking (and other potential confounders) in the analyses did not appreciably alter the risks seen for DDT, DDD, or Ethylan. CONCLUSIONS: Exposure to DDT was associated with pancreatic cancer. The association was not explained by exposure to lifestyle factors or other chemicals, and risk increased with both duration of exposure and latency since first exposure. IMPLICATIONS: These results may indicate that DDT can cause pancreatic cancer in humans under circumstances of heavy and prolonged exposure.

Familial risk of pancreatic cancer.

BACKGROUND: Pancreatic cancer is the fifth leading cause of cancer-related mortality in the United STATES: Although smoking and age are known risk factors for pancreatic cancer, several case reports and case-control studies have suggested that there is also a familial risk. We evaluated whether a family history of pancreatic cancer increases the risk of pancreatic cancer in first-degree relatives and whether smoking and younger age at cancer diagnosis further increase this risk. METHODS: We conducted in-person interviews with 247 patients ("case probands") with pancreatic cancer and 420 population-based control probands to collect risk factor data and pancreatic cancer family history for 1816 first-degree relatives of the case probands and 3157 first-degree relatives of the control probands. We analyzed the data by unconditional logistic regression models, with adjustment for correlated data by use of generalized estimating equations. All statistical tests were two-sided. RESULTS: A positive family history of pancreatic cancer (i.e., being related to a case proband) or ever-smoking cigarettes approximately doubled the risk of pancreatic cancer (relative risk [RR] = 2.49; 95% confidence interval [CI] = 1.32 to 4.69; RR = 2.04; 95% CI = 1.09 to 3.83, respectively). The RR increased to 8.23 (95% CI = 2.18 to 31.07) for relatives who ever smoked and were related to a case proband who was diagnosed before age 60 years. CONCLUSION: Routine questioning of patients about a family history of pancreatic cancer, the age of onset of this cancer in their relatives, and the patient's smoking status may identify individuals at high risk of pancreatic cancer. Future research exploring the genetic and environmental interactions associated with the risk of pancreatic cancer is critically important.

Tobacco, alcohol, diet, occupation, and carcinoma of the esophagus.

Information on occupation, smoking, food and beverage consumption, and medical history were compared between 275 incident cases of carcinoma of the esophagus and 275 neighborhood controls who were matched to the cases on age (within 5 years), race, and sex. Tobacco use, mainly cigarette smoking, was a significant risk factor for carcinoma of the esophagus. Ex-smokers of cigarettes showed a reduced risk relative to those who continued to smoke, and current smokers of two or more packs per day displayed a higher risk than those who smoked less. Alcohol consumption was another significant risk factor for carcinoma of the esophagus; there was a highly significant trend with average daily dose of ethanol. Relative to controls, cases also consumed significantly more fried bacon or ham, less fresh fruits and raw vegetables, and were more likely to prefer white than whole grain bread. Finally, there was a significant association between carcinoma of the esophagus and long-term occupational exposure to metal dust; this association was largely confined to the lower one-third section of the esophagus.

A case-control study of occupational and dietary factors in colorectal cancer in young men by subsite.

With the hope that exposures responsible for colorectal cancer might be especially obvious among those in whom it develops early, 147 men with colorectal carcinomas first diagnosed between the ages of 25 and 44 years were compared to neighborhood controls. Physical activity on the job was protective for tumors located in the transverse and descending portions of the colon. Rectal cancer and to a lesser extent sigmoid cancers were associated with jobs in which dusts or fumes were inhaled, especially if those jobs were held for long periods in young adulthood. While risk for rectal cancer did not seem to be limited to any particular type of dust or fume, the excess risk was strongest for wood and metal dusts. Consumption of fruits and vegetables and a preference for whole grain breads were protective for colon but not rectal cancers, while consumption of deep fried foods and barbecued/smoked meats increased risk at specific subsites. Beef intake, alcohol consumption, and cigarette smoking appeared to play little or no role at any subsite.

Occupational exposures of parents of children with acute nonlymphocytic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group conducted a case-control study of occupational exposures of parents of 204 children (under 18 yr of age) with acute nonlymphoblastic leukemia. The most consistent finding was an association of acute nonlymphoblastic leukemia risk with pesticide exposure. Controls matched by date of birth and race were obtained through random digit dialing. Odds ratio (OR) for paternal pesticide exposure in jobs held for longer than 1000 days was 2.7 (95% confidence interval, 1.0 to 7.0; trend, P = 0.06), and seven case mothers and no control mothers had prolonged exposure (trend, P = 0.008). Risk estimates for parental pesticide exposure were substantially increased for children under age 6 at diagnosis (OR for prolonged exposure to either parent = 11.4; trend, P = 0.003) and for those with myelomonocytic and monocytic subtypes (OR, 13.6; trend, P = 0.007). Moreover, there were significantly elevated risks for direct exposure of the child to pesticides in the household (OR for exposure most days = 3.5; trend, P = 0.04) and for maternal exposure to household pesticides at the time of pregnancy (eight case mothers versus no controls for exposure most days; trend, P = 0.05). Paternal exposures to solvents (OR, 2.1; P = 0.003) and petroleum products (OR, 2.4; P = 0.002) were reported more commonly for cases than controls. Other occupational exposures reported significantly more often by case parents were paternal exposure to plastics or lead and maternal exposure to paints and pigments, metal dusts, and sawdust. These data provide further evidence for a role of occupational risk factors in the etiology of childhood cancer.

Acute and chronic respiratory effects of sodium borate particulate exposures.

This study examined work-related chronic abnormality in pulmonary function and work-related acute irritant symptoms associated with exposure to borate dust in mining and processing operations. Chronic effects were examined by pulmonary function at the beginning and end of a 7-year interval. Time-specific estimates of sodium borate particulate exposures were used to estimate cumulative exposure during the study interval. Change in pulmonary function over the 7 years was found unrelated to the estimate of cumulative exposure during that interval. Exposure-response associations also were examined with respect to short-term peak exposures and incidence of five symptoms of acute respiratory irritation. Hourly measures of health outcome and continuous measures of particulate exposure were made on each subject throughout the day. Whenever a subject reported one of the irritant symptoms, a symptom intensity score was also recorded along with the approximate time of onset. The findings indicated that exposure-response relationships were present for each of the specific symptoms at several symptom intensity levels. The associations were present when exposure was estimated by both day-long and short-term (15-min) time-weighted average exposures. Associations persisted after taking account of smoking, age, and the presence of a common cold. No significant difference in response rate was found between workers exposed to different types of sodium borate dusts.

Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand.

We studied whether exposure to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War is related to peripheral neuropathy. The index subjects were veterans of Operation Ranch Hand, the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. We report peripheral nerve function assessed in 1982, 1985, 1987, 1992 and 1997, nerve conduction velocities measured in 1982, and vibrotactile thresholds of the great toes measured in 1992 and 1997. We assigned each Ranch Hand veteran to one of three exposure categories named "background", "low" and "high", based on his serum dioxin level. Other than the bilateral vibrotactile abnormalities, we consistently found a statistically significant increased risk of all indices of peripheral neuropathy among Ranch Hand veterans in the high exposure category in 1997, and a statistically significant increased risk of diagnosed peripheral neuropathy, incorporating bilateral vibrotactile abnormalities of the great toes, in the high category in 1992. Restricting to the enlisted veterans did not alter these results. Cautious interpretation of these results is appropriate until the relationship between pre-clinical diabetes mellitus and peripheral neuropathy is further evaluated in future examinations.

The effects of occupational exposure to chlorpyrifos on the peripheral nervous system: a prospective cohort study.

AIMS: To determine whether chronic occupational exposure to chlorpyrifos at levels associated with various aspects of manufacturing produced a clinically evident or subclinical peripheral neuropathy. METHODS: Clinical and quantitative nerve conduction study (NCS) examinations were performed on two occasions on chlorpyrifos manufacturing workers who had measurable chlorpyrifos exposure and a referent group. Baseline evaluations were performed on 53 of 66 eligible chlorpyrifos subjects and on 60 of 74 eligible referent subjects; one-year evaluations were completed on 111 of the 113 subjects evaluated at baseline. RESULTS: Chlorpyrifos and referent groups differed significantly in measures of 3,5,6 trichloro-2-pyridinol excretion and plasma butyrylcholinesterase (BuChE) activity, indicating substantially higher exposures among chlorpyrifos subjects. Few subjects had clinically important neurological symptoms or signs. NCS results were comparable to control values, and there were no significant group differences in NCS results at baseline, one year, or change over one year. No chlorpyrifos subject fulfilled conventional criteria for confirmed peripheral neuropathy at baseline or one-year examinations. The odds ratios for developing any diagnosable level of peripheral neuropathy among the chlorpyrifos subjects was not increased at baseline or at one year compared to referents at baseline. Mixed regression models used to evaluate subclinical group-by-time interactions showed numerous significant NCS differences attributable to near-nerve temperature differences among all subjects between the baseline and one-year examinations, but only a few disparate effects related to group. CONCLUSIONS: Chronic chlorpyrifos exposure during the manufacturing process sufficient to produce biological effects on BuChE activity was not associated with clinically evident or subclinical peripheral neuropathy at baseline or with measurable deterioration among chlorpyrifos subjects compared to referents after one year of additional exposure.

Epidemiologic principles in the evaluation of suspected neurotoxic disorders.

Epidemiology is the study of the patterns of disease and patterns of exposures in human populations. The main goals of epidemiology are to determine whether specific population groups have an increased risk of developing particular diseases and to determine what factors may be associated with increased risks of disease. In this article, the author focuses on epidemiologic studies of potential neurotoxic exposures, reviewing the basic principles involved and the special challenges associated with providing evidence of causal relationships between exposure and adverse health conditions.

Effectiveness of nicotine patches in a workplace smoking cessation program. An eleven-month follow-up study.

Transdermal nicotine patches are widely prescribed as part of smoking cessation programs, but their efficacy beyond 6 months is not well established. We evaluated the efficacy of a 70-day treatment regimen among 75 subjects in an industrial setting where follow-up was conducted for 11 months. The median time free of cigarettes was 73 days, and the overall smoking abstinence rate was 9% after 11 months of follow-up. Smoking abstinence was significantly higher among those subjects who completed the full course of treatment than among those who did not (25 vs 6%, respectively). Smoking abstinence was also higher among subjects who started smoking after age 17 than among those who started at younger ages and was higher among male than female subjects. We conclude that transdermal nicotine patches are of limited efficacy in achieving long-term smoking cessation and that the relative costs and benefits of this treatment are not adequately specified.

Neurologic evaluation of workers previously diagnosed with solvent-induced toxic encephalopathy.

We examined 52 railroad workers with long-term occupational solvent exposures (average 22 years duration) who had been previously diagnosed by others as having solvent-induced toxic encephalopathy. All described episodes of transient intoxication associated with occupational solvent exposure. Persistent symptoms developed, an average, 16 years after exposure onset and included impaired memory (38), altered mood (21), imbalance (18), and headache (17). Thirteen workers had mild mental status abnormalities, but none fulfilled conventional clinical criteria for encephalopathy or dementia. None had abnormal blink reflex (51) or abnormal electroencephalographic (39) studies. Eight of 47 magnetic resonance imaging studies showed evidence of scattered ischemic lesions among workers with known diabetes mellitus (2), elevated blood pressure (4), or peripheral vascular disease (2). One magnetic resonance imaging scan showed mild cortical atrophy. In stepwise multiple linear and logistic regression models, no statistically significant (P < 0.05) dose-response relationships were found between exposure duration and symptoms or signs that were suggestive of encephalopathy. However, the number of symptoms (P < 0.001) and the number of signs (P = 0.05) were associated with current use of central nervous system-active medications. Further, lower Mini-Mental Status Examination scores were associated with a history of alcohol abuse (P = 0.01) and lower educational level (P = 0.03). The number of chief symptoms involving memory, mood, balance, or headache differed significantly among workers in different geographic sites (F(3.48) = 2.94, P = 0.04), a finding that was not explained by job title or exposure duration. There also was a significant (P = 0.0001) inverse relationship between initial exposure year (r2 = 0.60) or total years of exposure through 1987 (r2 = 0.56) and interval to major neurologic symptom onset, suggesting that factors other than solvent exposure account in part for worker complaints. We found no objective neurologic evidence supportive of toxic encephalopathy or any other uniform syndrome among these individuals, and most complaints were explained by neuropsychological factors or conditions unrelated to occupational solvent exposure.

Comparison of surrogate with self-respondents for occupational factors.

Accurate assessment of occupational history is critical in case-control studies of disease risk associated with employment. However, in some studies of rapidly fatal diseases, a surrogate or next of kin is interviewed rather than the study subject. In a unique re-interview study of subjects from a community-based case-control study originally interviewed 5 years earlier, we evaluated the level of agreement between (1) subjects and their surrogates on re-interview among those who had died since the first interview, and (2) subjects themselves and their responses at re-interview among those still living (to use as a comparison) regarding work history and specific occupational exposures. For employment start and stop dates, number of years worked, and number of jobs reported in the 1980 interview, exact agreement was poor for surrogate respondents and for self-respondents in the re-interview, with percentages ranging from 4% to 40%. Agreement was similar for surrogates and self-respondents for job and industry worked the longest, but percent of agreement among surrogates was significantly lower than among the self-respondents for job and industry worked last. Five (28%) of the kappa values for the industry in which the subject worked had high agreement (kappa > 0.75) for self-respondents and surrogates. None of the kappa statistics for materials handled by subjects in their jobs had high agreement, and 57% of the kappa statistics had poor agreement (kappa 0.0 to 0.39). This study suggests that occupational histories obtained by interview are poorly reproduced, and existing methods may need improvement to collect reliable occupational data. Further, the findings indicate that caution should be exercised when creating a job-exposure matrix based on such data.

Evaluation of blink reflex results obtained from workers previously diagnosed with solvent-induced toxic encephalopathy.

We reviewed blink reflexes recorded from 51 railroad workers with long-term occupational exposure to solvents who were diagnosed by others with solvent-induced toxic encephalopathy. No worker fulfilled conventional clinical criteria for dementia or trigeminal mononeuropathy. All workers had normal R1 and R2 blink reflex latencies. R1 latencies correlated significantly with several nerve conduction measures, including F wave latencies, suggesting that some intersubject variability reflected intrinsic conduction properties, not isolated brain-stem function. Although normal, the workers' R1 latencies were significantly prolonged compared with historical control groups, including gender-matched control subjects of similar mean age (11.2 ms vs 9.9 ms; P < 0.0001). Stepwise multiple regression models demonstrated significant associations of R1 latency with age and use of CNS-active prescription medications (P = 0.003), but duration of occupational solvent exposure did not enter into the models. Paradoxically, workers using CNS-active medications had significantly shorter R1 latencies compared with workers not using such medications (10.9 vs 11.7 ms; P = 0.01). Job title, another potential surrogate measure of exposure, was not significantly related to reflex latencies. The geographical site of predominant solvent exposure did influence R1 latency, and workers from one site had longer exposure duration and longer R1 latencies than remaining workers. However, an interaction between age and exposure duration (r = 0.39; P = 0.003) confounded interpretation of this observation. Disability or work status, mental status findings, or classification of encephalopathy did not influence blink reflex latencies. The overall results do not support, but do not entirely exclude, a possible relationship between subclinical blink reflex abnormalities and occupational exposure to solvents. Nevertheless, it is clear from these results that the small group differences in R1 latency between exposed workers and control subjects are of no diagnostic importance and of uncertain physiologic importance, and they may reflect unrecognized confounders and technical factors.

Abnormalities of pulmonary function and pleural disease among titanium metal production workers.

The authors conducted a cross-sectional survey of respiratory disease among 209 titanium metal production workers. Work in areas where there was exposure to titanium tetrachloride and titanium dioxide particulates was associated with reductions in ventilatory capacity. Pleural disease (plaques and diffuse thickening) was present in the chest radiographs of 17% of the subjects and was associated with the duration of work in titanium manufacturing. It was also associated with past asbestos exposure. After control for asbestos exposure, it remained associated with titanium manufacturing. The findings are consistent with the hypothesis that titanium tetrachloride and titanium dioxide particulates may be associated with a reduction in ventilatory capacity and that the overall process of titanium manufacturing may be associated with unexpected pleural disease.

Wood-dust exposures and cancer of the colon.

Previous studies of workers exposed to wood dusts have shown a decreased risk of cancer of the colon in these workers. However, none of these studies adequately controlled for potential confounders, such as physical activity, diet, and family history of colorectal cancer. The purpose of this case-control study was to evaluate the association between exposure to wood dust and risk for colon cancer after adjusting for potential confounders. Four hundred nineteen male cases of adenocarcinoma of the colon, identified from the Los Angeles County Cancer Surveillance Program, were individually matched to neighborhood controls based on gender and date of birth. Exposure to wood dust was associated with reduced risk of colon cancer that was partially masked before adjustment for confounders, and was limited to workers with frequent exposures that had begun at least 30 years before diagnosis [unadjusted and adjusted ORs, respectively, to exposures 5+ times a week beginning 30+ years before diagnosis = 0.63 (95% CI 0.36-1.13) and 0.39 (95% CI 0.20-0.77)]. This study provides additional evidence that heavy exposure to wood dusts may be associated with reduced risk of colon cancer in males after adjustment for other known causes of colon cancer.

Occupational cancer.

Occupational exposures are important contributors to the total burden of cancer in the United States. No histologic features distinguish occupational cancer from that due to other causes. The IARC provides a systematic framework for evaluating the evidence linking occupational exposures to human cancer and publishes summary monographs which detail the strength of evidence for approximately 732 agents evaluated to date. These monographs are one of the most reliable reference sources for practitioners who must answer questions regarding cancer risk to working populations. The diagnosis of occupational cancer must be based on a systematic approach in which the diagnosis of cancer is confirmed, the exposures of the patient are defined and quantified, and the scientific evidence regarding the risk from such exposures is evaluated. Cancer screening programs in work settings are difficult to justify based on scientific principles and must be adapted to the circumstances of exposure and to meet legal requirements for medical surveillance, if they are to be performed at all. Investigation of cancer clusters often presents a difficult scientific challenge, which requires careful case ascertainment, calculations of risk based on an appropriate reference population, identification of distant past exposures, and a search for common elements among the cases. Negative and equivocal findings are common, and it is important for investigators to be able to demonstrate the scientific rigor of their approach in resolving these issues.

Dermatitis from aziridine hardener in printing ink.

13 of 51 workers developed dermatitis of the hands and face after handling a water-based ink containing a polyfunctional aziridine hardening agent. Improper work practices resulted in skin contamination with the ink and its ingredients. The aziridine hardener contained trimethylolpropane triacrylate (TMPTA). The incidence of dermatitis was highest among the ink mixers who handled the undiluted aziridine (6 of 8 workers affected), was lower among printers who handled ink containing 2 to 4% aziridine (7 of 22 workers affected), and was absent in workers who did not handle ink. The mean latency from first contact with the ink to the development of the rash was 3.2 months among the ink mixers, and 6.2 months among the printers. The present findings demonstrate the risk of handling aziridine hardeners when protective clothing is not properly used and when work practices result in direct skin contact. Further research should be performed to discern whether aziridine compounds themselves, free of TMPTA, can cause dermatitis.

Cancer mortality among shoe and leather workers in Massachusetts.

A proportional mortality analysis of death certificates of 2,798 shoe and leather workers demonstrated a statistically significant excess of bladder cancer among female shoe workers (PMR = 2.51, 95% confidence interval 1.23 to 5.12). A case-referent analysis of 289 leather workers, on whom detailed occupational information was available, demonstrated an association of lung cancer with work in leather-tanning jobs (odds ratio = 4.2, 95% confidence interval 1.09 to 16.2).

Carcinogens and cancer risks in the microelectronics industry.

Additional epidemiologic studies and a systematic program of carcinogenicity testing of materials are necessary to demonstrate that the electronics industry is free of cancer risks. Screening of new and existing materials for mutagenic activity is needed before these materials are introduced into the workplace. Materials found to possess mutagenic activity should be more extensively tested in animals so that their carcinogenic potential can be defined. Those found to be carcinogenic in animals should be regarded as though they are carcinogenic to humans.

Epidemiology of organic solvents and connective tissue disease.

Case reports suggest that solvents are associated with various connective tissue diseases (systemic sclerosis, scleroderma, undifferentiated connective tissue disease, systemic lupus erythematosis, and rheumatoid arthritis), particularly systemic sclerosis. A small number of epidemiological studies have shown statistically significant but weak associations between solvent exposure, systemic sclerosis, and undifferentiated connective tissue disease. However, the interpretation of these positive findings is tempered by a lack of replication, an inability to specify which solvents convey risk, and an absence of increasing risk with increasing exposure. Existing studies, on aggregate, do not show conclusively that solvents (either as a group of chemicals or individual chemicals) are causally associated with any connective tissue disease. Further investigations should be carried out to replicate the positive existing findings and to specify the solvents and circumstances of exposure that carry risk.