Cancer incidence rates among Lawrence Livermore National Laboratory (LLNL) employees: 1974-1997.

BACKGROUND: In the mid-1970's an excess of malignant melanoma of the skin was noted among employees at the Lawrence Livermore National Laboratory (LLNL). A 1984 cancer incidence study showed a non-significant excess of total cancers among female employees with significant excesses for melanoma, rectum and anus, and salivary gland cancers. For male employees, there was a non-significant deficit of total cancer with significant excesses in melanoma and non-brain nervous system cancers. This paper reports the results of a surveillance effort to update our understanding of the patterns of cancer incidence in this population. METHODS: We used California Cancer Registry (CCR) data to ascertain employees who had worked for six or more consecutive months at LLNL during the 24-year period of 1974 through 1997 who were diagnosed weith cancer during that time frame. We used the Standardized Incidence Ratio (SIR) in our analyses. RESULTS: There were 17,785 employees who provided 186,558 person-years of observation: 145,203 were from males and 41,355 were from females. The CCR, through its linkage techniques, identified 541 individuals with invasive cancer and 96 with in situ cancer. A total of 404 males had invasive cancer and 33 had in situ cancer whereas there were 137 females with invasive cancer and 63 with in situ cancer. The SIR for invasive cancer in males was 69 (95% CI 62-76). The overall cancer SIR for males was unaffected by calendar time. There were only two invasive cancer sites with significant excess: melanoma and cancer of the testes. For eight categories or cancer sites, we found a statistical deficit in cancer incidence. The most striking deficit occurred in cancer of the lungs and bronchus with a SIR of 36 (95% CI 26-50). The SIR for invasive cancer in females was 80 (95% CI 67-94). The overall cancer SIR for females decreased over calendar time. There was a statistically significant deficit for cancers of the female genital organs. There were 84 cases of invasive and in situ melanoma in both genders. Time-trend analyses for melanoma showed a significant excess during the years 1974-1985 but a reduction to community rates from 1986 through 1997. There were 21 individuals with testicular cancer with a SIR of 207 (95% CI 129-317). There were no differences in age at diagnosis or cell type with the comparison population. We analyzed the data using the same radiosensitive cancer categories used in the 1984 study. There were no increases in SIRs in any of these categories. CONCLUSIONS: We found that the LLNL employees had less cancer than expected with males having relatively fewer cancers than females. The lung cancer rate for males was remarkably low. Since 1986 the melanoma rates resemble the community rates. Testicular cancer rates are modestly elevated and appear to have been so for the past 20 years. Lifestyle patterns, including smoking, and cancer screening activities are probably important contributors to the observed low cancer rates.

Nonpeptide CXCR2 antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats.

Neutrophil influx in lung injury is controlled in part by chemokines acting through the receptor, CXCR2. To avoid adverse effects of steroids typically used to modify inflammation, we evaluated the effects of competitive blockade of CXCR2 in rats on neutrophil function in vitro and on neutrophil influx in vivo in hyperoxia-induced newborn lung injury, a model of bronchopulmonary dysplasia. In vitro, SB-265610 antagonizes rat cytokine-induced neutrophil chemoattractant-1 (CINC-1)-induced calcium mobilization, IC50 = 3.7 nM, and rat neutrophil chemotaxis in a concentration-dependent manner, IC50 = 70 nM. In vivo, newborn rats exposed to 95% O2 for 8 days had increased lung neutrophil content. Injection with 1 to 3 mg/kg SB-265610 on days 3 to 5 reduced hyperoxia-induced neutrophil accumulation in bronchoalveolar lavage and whole lung myeloperoxidase accumulation at the highest doses. To determine whether these effects might be due in part to increased neutrophil apoptosis, peripheral neutrophils were cultured with and without SB-265610. Apoptosis was assessed by morphology, viability, and terminal transferase deoxyuridine triphosphatidyl nucleotide nick-end labeling. Treatment of neutrophils with CINC-1 reduced apoptosis compared with untreated neutrophils. SB-265610 reduced the antiapoptotic effect of CINC-1 to the levels of those untreated with CINC-1. A selective CXCR2 antagonist may be useful in diseases where neutrophil-mediated exacerbation is present.

Anti-neutrophil chemokine preserves alveolar development in hyperoxia-exposed newborn rats.

Inflammation may contribute to lung injury and impaired alveolar development in bronchopulmonary dysplasia. We treated hyperoxia-exposed newborn rats with antibodies to the neutrophil chemokine cytokine-induced neutrophil chemoattractant-1 (CINC-1) during 95% O2 exposure to reduce adverse effects of hyperoxia-induced inflammation on lung development. Rats were exposed at birth to air, 95% O2, or 95% O2 + anti-CINC-1 (injected on days 3 and 4). Bromodeoxyuridine (BrdU) was injected 6 h before death. Anti-CINC-1 treatment improved weight gain but not survival at day 8. Anti-CINC-1 reduced bronchoalveolar lavage neutrophils at day 8 to levels equal to air controls. Total detectable lung CINC-1 was reduced to air control levels. Lung compliance was improved by anti-CINC-1, achieving air control levels in the 10-microg anti-CINC-1 group. Anti-CINC-1 preserved proliferating cell nuclear antigen expression in airway epithelium despite 95% O2 exposure. BrdU incorporation was depressed by hyperoxia but preserved by anti-CINC-1 to levels similar to air control. Alveolar volume and surface density were decreased by hyperoxia but preserved by anti-CINC-1 to levels equal to air control. Blockade of neutrophil influx in newborns may avert early lung injury and avoid alveolar developmental arrest that contributes to bronchopulmonary dysplasia.

Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations.

Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent.

Thrombophilic DNA Mutations As Independent Risk Factors for Stroke and Avascular Necrosis in Sickle Cell Anemia.

Thrombosis may be important in the pathophysiology of certain complications of sickle cell anemia (SCA), including cerebrovascular accident (CVA, stroke) and avascular necrosis (AVN). No single laboratory or clinical parameter can accurately identify patients who will develop these thrombotic complications. We hypothesized that a subset of patients with SCA have genetic thrombophilic mutations that increase the risk of stroke or AVN. We examined nine known thrombophilic DNA polymorphisms in α-fibrinogen, ß-fibrinogen, platelet glycoprotein IIIa, Factor VII, methylenetetra-hydrofolate reductase, plasminogen activator inhibitor-1, prothrombin, and Factor V genes in 101 African-American patients with SCA (27 CVA, 16 AVN). The allele frequency of thrombophilic mutations ranged from 0.0 (Prothrombin, Factor V) to 0.33 (α-fibrinogen). No mutation was significantly more common in patients with CVA or AVN than in patients without these complications. These nine thrombophilic mutations do not appear to be significant risk factors for the development of clinically overt CVA or AVN in SCA.

Cohort mortality study of prostate cancer among chemical workers.

A retrospective cohort mortality study was conducted at a chemical plant producing acetic acid and acetic anhydride, two chemicals essential in the synthesis of cellulose triacetate fiber. Previously, we reported excess mortality from biliary tract and prostate cancers among workers in cellulose triacetate fiber manufacturing plants. In the present investigation, an excess of prostate cancer (SMR = 330.4; 95% confidence interval = 121.3-719.1) was observed among former chemical plant workers, some of whom had been exposed to both acetic acid and acetic anhydride. These apparent increases in mortality are difficult to interpret biologically, particularly in light of recent suggestions concerning the role of endocrine factors. Additional work is planned to more fully characterize potential occupational exposures that might explain the etiology of prostate cancer.

Reproductive effects of sodium borates on male employees: birth rate assessment.

OBJECTIVES: The purpose of the study was to investigate potential reproductive effects of sodium borates on occupationally exposed male employees at a large mining and production facility in the Mojave Desert of California. METHODS: The standardised birth ratio (SBR) was used to assess fertility of the male employees. Live births were the measured end point, and the rate of female to male offspring was also assessed. Data were collected through a questionnaire after a series of on site introductory and explanatory meetings with the employees. Initial non-responders were followed up by telephone. Medical insurance records were assessed for those who declined to participate. RESULTS: The questionnaire was a good method of ascertainment for live births. There was no evidence of selection bias in the results. There was a highly significant excess of offspring fathered by the male employees. There was no evidence of a relation between exposure and this excess of offspring, nor were there any temporal differences during the period of observation (> 30 years). Also, there was an excess of the percentage of female offspring fathered by these male employees. This excess of female offspring was not significant. There was no evidence of an exposure relation to sodium borates with this excess of female offspring nor were there any temporal differences. CONCLUSION: Under the conditions studied, there were no adverse reproductive effects of high borate doses as reported from oral ingestion studies in animals.

An updated cohort mortality study of workers exposed to styrene in the reinforced plastics and composites industry.

Mortality data have been updated for a further 12 years for a cohort of workers in the reinforced plastics and composites industry with exposures to styrene monomer and other chemicals. The cohort consisted of 15,826 male and female employees who were exposed to styrene for at least six months between 1948 and 1977 at 30 participating manufacturing plants in the United States. A total of 1628 deaths were reported during the extended observation period, 1948-89. Mortality from several causes showed significant increases--namely, all causes, all cancers, oesophageal cancer, lung cancer, cancer of the cervix uteri, cancer of other female genital organs, hypertensive heart disease, certain non-malignant respiratory diseases, motor vehicle accidents, and homicides. When, however, mortality data were examined in terms of duration of employment, durations of styrene exposure, and cumulative styrene exposure no upward trend was detected in any of these causes of death. Most of the increases in mortality were among workers who were employed for only six months to a year or who had very low cumulative exposure (< 10 ppm-years). Therefore, the increased mortality was not likely to be related to exposure to styrene. Several explanations for the increased mortality are offered, including low socioeconomic class, smoking, and lifestyle factors characteristic of short term workers. There was no increased mortality from lymphatic and haematopoietic cancers overall or from any specific haematological malignancies. In particular, no increase in mortality from non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or leukaemia was found. Furthermore, detailed exposure-response analyses did not show any relation between exposure to styrene and any of these haematological malignancies. The lack of an exposure-response relation further supports the conclusion that workers in the reinforced plastics industry in this study did not experience any increased risk of lymphatic and haematopoietic cancers as a result of their exposure to styrene.

An ecologic study of skin cancer and environmental arsenic exposure.

We conducted an epidemiologic study of skin cancer incidence rates for four counties in Montana. The two counties considered to be exposed to arsenic were Deer Lodge, containing the former Anaconda copper smelter, and Silver Bow, containing an open pit copper mine. Residents in these counties had potential exposure to arsenic and other heavy metals. Gallatin and Park counties served as controls. All histologically proven skin cancer cases during the period January 1980 through June 1986 were collected from pathology services and dermatologists in these four counties. In addition, all skin cancer cases from four dermatologists practicing in urban referral areas outside the counties were reviewed. Results were analyzed by individual as well as by two different definitions of anatomically distinct lesions: the National Cancer Institute (NCI) definition and the study definition. There were 1616 individuals with skin cancer in the four counties during the period under consideration, yielding 2252 (NCI definition) and 2451 (study definition) cases. The clinical features of the skin cancers in the exposed counties were not similar to those described for arsenic-related skin cancer. The age-adjusted annual skin cancer rates were higher for the two control counties as compared to either the county with the former smelter, Deer Lodge, or the county with the mine, Silver Bow. Our results cannot be explained by differences in ascertainment, latitude, or altitude. They can be partially explained by differences in both outdoor employment and medical practice. The overall skin cancer incidence rates for the exposed counties were well within the range of skin cancer rates observed for other locations in the United States.

An industry-wide epidemiologic study of vinyl chloride workers, 1942-1982.

The cohort consisted of 10,173 men who had worked for at least one year in jobs involving exposure to vinyl chloride prior to 1 January 1973. These men were employed at 37 plants in the U.S., belonging to 17 companies. Observation of the mortality experience of the cohort was updated from 31 December 1972 to 31 December 1982 (the study now covering 1942-1982). A total of 1,536 cohort members were identified as having died. The observed mortality, by cause, was compared with the expected based on U.S. mortality rates, standardized for age, race, and calendar time. Analyses by length of exposure, latency, age at first exposure, calendar year of first exposure, and type of products were performed. The study confirmed that the vinyl chloride workers experience a significant mortality excesses in angiosarcoma (15 deaths), cancer of the liver and biliary tract (SMR = 641), and cancer of the brain and other central nervous system (SMR = 180). In addition, the study also found a significant mortality excess in emphysema/chronic obstructive pulmonary disease (COPD) (SMR = 179). On the other hand, the study did not find any excess in either respiratory cancer or lymphatic and hematopoietic cancer. This study also found an increase in biliary tract cancers, independent from liver cancer.

Ecological analyses and case-control studies of gastric cancer and leukaemia in relation to DBCP in drinking water in Fresno County, California.

Through ecological analyses and case-control studies, the possible relation of gastric cancer and leukaemia to dibromochloropropane (DBCP) contamination of drinking water in Fresno County, California, has been examined. The ecological analyses examined the correlation between gastric cancer and leukaemia (including the lymphatic varieties), mortality rates, and DBCP concentrations in drinking water by census tract in Fresno County, 1960-83. No correlation was found between gastric cancer or leukaemia and DBCP. The gastric cancer case-control study consisted of 263 deaths from gastric cancer in the county, 1975 to mid-1984, and 1044 controls, using information on residential history and occupation of both cases and controls. Analyses were based on residence at death, as well as one and ten years before death. The case-control study did not find any relation between gastric cancer and DBCP in drinking water. Hispanics in the county were found to experience a relative risk of gastric cancer of 2.77, compared with non-Hispanics. A similar case-control study consisting of 259 cases of leukaemia and 1161 controls found no relation between all leukaemia or lymphatic leukaemia and DBCP in drinking water. Farm workers, however, do appear to have an increased risk of leukaemia.

An epidemiologic investigation of birth outcomes in relation to dibromochloropropane contamination in drinking water in Fresno County, California, USA.

This report describes an epidemiologic investigation of the relationship between dibromochloropropane (DBCP), contamination in drinking water and birth outcomes between 1978 and 1982 in Fresno County, California, USA. Census tracts in the county were categorized according to DBCP level in drinking water. A direct comparison between exposure categories was done by the use of the Mantel-Haenszel chi-square procedure to compute relative ratios or risks for low birth weight and birth defect, adjusting for age, race, percent Hispanic, and parity. No correlation between these birth outcomes and DBCP contamination was found. In addition, we did not find any difference in sex ratio in relation to DBCP contamination.

Problems associated with collecting drinking water quality data for community studies: a case example, Fresno County, California.

This paper discusses methodology in developing exposure data for the water supply contaminant dibromochloropropane (DBCP) in Fresno County, California. There are 532 drinking water systems (49 large and 483 small) within Fresno County plus 14,000 private wells. We determined the number of wells per system, the output per well, and the population served by each system. The task of deriving water quality estimates for each census tract was complicated by the fact that a single census tract can be served by more than one system; each system usually has more than one well; and a single well can have several episodes of testing for various contaminants. We calculated a series of weighted averages for concentrations of DBCP, arsenic, and nitrates for each census tract, using water production figures for each well as the weighting factor. Water quality data were derived from a total of 14,861 laboratory reports, although the majority did not report on all contaminants. Mean DBCP levels ranged from 0.0041 ppb to 5.7543 ppb among the census tracts. We found no correlation between DBCP levels per census tract compared to either arsenic or nitrates. We believe that we made as complete an exposure assessment as practically feasible.

An epidemiologic investigation of the relationship between DBCP contamination in drinking water and birth rates in Fresno County, California.

This report describes an epidemiologic investigation of the relationship between DBCP (dibromochloropropane) contamination in drinking water and birth rates between 1978 and 1982 in Fresno County, California. Census tracts in the county were categorized according to DBCP level in their drinking water. Standardized birth ratios and relative birth ratios (adjusted for age, race, per cent Hispanic, and parity) were calculated for these census tracts. No relation between birth ratios and DBCP contamination in drinking water was found.

Investigation and work-up of tight building syndrome.

In recent years, incidents involving health-related complaints due to poor indoor air quality have increased dramatically. These problems have generally occurred in new or remodeled buildings. Following relocation to a new building, some employees began to experience health complaints, including upper respiratory tract irritation, headaches, fatigue, and eye irritation. A questionnaire was designed which elicited information about specific work locations, symptom experience, and timing of such symptoms. Although no causative agent(s) could be isolated, the data collected indicate that over the 5-week time period of investigation the rate and persistence of new symptoms decreased. The health complaints experienced appeared to be neither persistent nor pervasive enough to constitute an ongoing health and safety hazard at the facility. Reasons were proposed why some new and/or remodeled buildings have this type of problem while others do not.

Seven-year follow-up of workers exposed to 1,2-dibromo-3-chloropropane.

A follow-up report was done of workers exposed to 1,2-dibromo-3-chloropropane (DBCP) 7 years after termination of exposure. A 1977 study of male pesticide workers exposed to DBCP in a California agricultural chemical plant identified many who were azoospermic or oligospermic. Sperm concentration and serum follicle-stimulating hormone (FSH) levels in 44 of these workers were reassessed 5 to 8 years after exposure was terminated in 1977. Two of the eight originally azoospermic workers produced sperm during the follow-up, although only one had normal sperm counts. No increase in sperm production could be detected in men who had low sperm counts in 1977, and elevated serum FSH levels did not drop in oligospermic or azoospermic men. These results suggest that permanent destruction of germinal epithelium occurs in most DBCP-sterile persons.

Male reproductive hazards.

Studies of adverse reproductive effects on male workers have only become prominent in the last 10 years and have used a variety of approaches to evaluate male reproductive function. This article focuses on studies that utilize semen analysis.

Mortality among members of a heavy construction equipment operators union with potential exposure to diesel exhaust emissions.

A historical prospective mortality study was conducted on a cohort of 34 156 male members of a heavy construction equipment operators union with potential exposure to diesel exhaust emissions. This cohort comprised all individuals who were members of the International Union of Operating Engineers, Locals 3 and 3A, for at least one year between 1 January 1964 and 31 December 1978. The mortality experience of the entire cohort and several subcohorts was compared with that of United States white men, adjusted for age and calendar time. The comparison statistic was the commonly used standardised mortality ratio (SMR). Historical environmental measurements did not exist, but partial work histories were available for some cohort members through the union dispatch computer tapes. An attempt was made to relate mortality experience to the union members' dispatch histories. Overall mortality for the entire cohort and several subgroups was significantly lower than expected. When cause specific mortality was examined, however, the study provided suggestive evidence for the existence of several potential health problems in this cohort. Mortality from liver cancer for the entire cohort was significantly high. Although mortality from lung cancer for the entire cohort was similar to expected, a positive trend by latency was observed for lung cancer. A significant excess of mortality from lung cancer was found among the retirees and the group for whom no dispatch histories were available. Other dispatch groups showed no evidence of lung cancer excess. In addition, the total cohort experienced significant mortality excess from emphysema and accidental deaths.