Butadiene cancer exposure-response modeling: based on workers in the styrene-butadiene-rubber industry: total leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.

Cox regression is used to estimate exposure-response models (with cumulative 1,3-butadiene (BD) ppm-years as the exposure metric) based on the most recent data and validated exposure estimates from UAB's study of North American workers in the styrene-butadiene-rubber industry. These data are substantially updated from those in USEPA's 2002 risk assessment. The slope for cumulative BD ppm-years is not statistically significantly different than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined (total leukemia). For total leukemia, the EC(1/100,000) is approximately 0.15 BD environmental ppm and the corresponding unit risk factor is approximately 0.00007 per BD environmental ppm. The excess risk for CML is approximately 15-fold less than for total leukemia. The maximum likelihood estimates suggest that there is no excess risk for AML from cumulative BD ppm-years. For CLL, the slope is statistically significantly different than zero. The excess risk for CLL is approximately 2.5-fold less than for total leukemia. For both total leukemia and CLL, the slope is not statistically significantly different than zero when the exposure-response modeling is based on the person-years with cumulative BD ppm-years less than or equal to 300 ppm-years.

Lymphohematopoietic cancers and butadiene and styrene exposure in synthetic rubber manufacture.

The described nested case-control study of lymphohematopoietic cancers occurring in a cohort of synthetic rubber production workers was conducted to determine the associations of these cancers with exposure to butadiene and styrene. Cases have been confirmed through hospital record review of 95 percent of the cancers. Exposures are based on measured values of the two chemicals from personal monitoring data in seven of the eight plants under study. The results indicate that the risk of leukemia increases with exposure to a time-weighted average butadiene measure. The odds ratio at only 1 ppm average butadiene exposure is 1.50 (95% CI 1.07, 2.10). Work in specific areas also contributes to the risk, possibly because these areas have not been completely characterized for differences in butadiene exposure. Hodgkins disease is also associated with butadiene exposure. Multiple myeloma, lymphosarcoma, and all lymphomas are associated with exposure to styrene. Since workers in this industry are apparently exposed to two carcinogenic agents, further effort must be made to distinguish the exposures to each chemical over time and to characterize their interrelationship with the risk of cancers of the lymphohematopoietic system.

Monitoring of styrene exposure in the polyester industry.

Obtaining reliable results of exposure to styrene in field studies requires an appropriate methodology not only for analytical methods but also for the main strategy of conducting the surveys. This paper briefly describes how and why analytical methods for styrene in air, for its main metabolites in urine (mandelic and phenylglyoxylic acids) and for critical biological function tests were either chosen from the literature or adapted or developed to fit our criteria of convenience and reliability. In a second step of the preparation of field studies, experimental exposures to styrene were carried out on volunteers so that the best indicators of exposure could be determined and data could be obtained on the elimination kinetics of the urinary metabolites and the quantitative relationships between exposure and the urinary concentrations of mandelic and phenylglyoxylic acids. Finally field investigations, including air and biological monitoring, complete industrial hygiene surveys and medical examinations, have been organized and are being carried out in the Swiss polyester industry. Preliminary results concerning biological monitoring are given.

Mutagenicity study of workers employed in the styrene and polystyrene processing and manufacturing industry.

Mutagenicity studies were undertaken on lymphocytes from the following groups of persons exposed to styrene or polystyrene: one group from a styrene manufacturing plant, one from a polystyrene plant, and three from plants processing unsaturated polyester resins with different manufacturing methods. For all the groups the concentration of styrene in the atmosphere of the workplace was measured at various points and the amount of urinary mandelic acid was determined. In each case 100 metaphases were analyzed for chromosomal aberrations. The results were compared with reference groups.

Disturbances in psychological functions of workers occupationally exposed to styrene.

The relationship between long-term occupational styrene exposure and disturbances in psychological functions was studied. The exposed group consisted of 98 male workers exposed to styrene in the manufacture of polyester plastic products, and the comparison group comprised 43 concrete reinforcement workers. The duration of exposure in years and the mean mandelic acid concentration in urine (five determinations during 5 weeks before the clinical examination) and the cumulative dose of exposure were used as the indicators of exposure. The psychological functions studied were intelligence, visuomotor speed, visuomotor accuracy, memory, vigilance, and psychomotor performance. Some personality test variables were also included. In a group comparison two variables (visuomotor inaccuracy and poor psychomotor performance) out of 20 showed statistically significant differences and characterized the styrene exposed group. These findings were confirmed when workers with low and high styrene exposure were compared. One variable measuring visuomotor speed and another measuring visual memory were related to the duration of exposure (R = 0.28, p less than 0.05). In a multiple regression analysis disturbances in visuomotor accuracy, poor psychomotor performance, and lowered vigilance proved to have some connection with a high mandelic acid concentration (R = 0.49, p less than 0.01). In addition workers with disturbances in visuomotor accuracy and slight disturbances in virumotor speed had higher mandelic acid concentrations when compared with those workers without any deterioration. The results indicate that disturbances in visuomotor accuracy and, to a lesser degree, in psychomotor performance are the main findings measured by test methods used in this study and related to one indicator of styrene exposure, mandelic acid concentration. The psychological methods used revealed subclinical symptoms related to exposure, and they should aid in making group diagnoses, e.g., when additional information is needed for the determination of the threshold limit value. The deterioration found in visuomotor accuracy could be related to lowered safety in work and traffic.

Neurophysiological findings among workers occupationally exposed to styrene.

Ninety-six male workers occupationally exposured to styrene in 24 plants producing reinforced polyester plastic products were studied neurophysiologically. The mean age of the subjects was 29.6 +/- 7.4 years, and the duration of the exposure varied from 6 months to 14 years (mean 5.0 years). Mandelic acid concentration in the urine (mean of five values determined during five consecutive weeks) was used as the measure of exposure. The individual means of the mandelic acid concentrations varied from 7 to 4,715 mg/dm3 (median 808 mg/dm3). Neurotoxic effects of styrene exposure upon the central nervous system were revealed by abnormalities in the EEG. The overall prevalence of abnormal EEGs was 24% (23 out of 96), which is higher than that found among a normal population (p less than 0.05). Abnormal EEGs were found in one-third of the subjects with relevant styrene exposure (mandelic acid concentration over 700 mg/dm3), while low-level styrene exposure did not increase the prevalence of normal EEGs above that found in a normal population. Nerve conduction velocity measurements performed on 40 subjects did not reveal any definite relationship between neuropathy and styrene exposure. The EEG examination is useful in the investigation of the neurotoxic effects of styrene. Whenever a possibility exists of excessive styrene exposure or beginning poisoning, the workers should be submitted to an EEG examination.

Epidemiologic investigations of styrene-butadiene rubber production and reinforced plastics production.

The United States National Institute for Occupational Safety and Health (NIOSH) began an epidemiologic study of workers employed in the styrene-butadiene rubber (SBR) industry during 1976. This study was prompted by reports of relatively high numbers of leukemia deaths occurring within SBR production work populations. Simultaneous with the initiation of this investigation, the University of North Carolina released a report associating an excess risk of death due to hematopoietic and lymphatic malignancies among workers producing several synthetic rubbers, including SBR. This report presents NIOSH's preliminary mortality observations and a discussion of progress made on the analyses of contaminants found in two SBR production facilities. Currently, NIOSH is determining the feasibility of doing an epidemiologic study in the reinforced plastics industry. Interest in this study developed as part of an effort to determine health hazards associated with occupational exposure to styrene. Most of the technology for the reinforced plastics industry developed in the 1950s, and therefore this process represents a relatively new industry. This report also includes information on environmental conditions observed in the reinforced plastics industry and enumerates some of the complicating characteristics of this industry which increase the complexity of this study.

Biological indicators of exposure in styrene polymerization workers. Styrene in blood and adipose tissue and mandelic and phenylglyoxylic acids in urine.

The concentrations of mandelic and phenylglyoxylic acids, urinary metabolites of styrene, and styrene in blood were determined for 491 styrene polymerization workers. Styrene in subcutaneous fat was determined for 25 workers. The levels of styrene exposure were estimated to be less than 10 ppm, and urinary metabolite and blood styrene concentrations indicated that significant recent exposure (within 4 h) had occurred among workers in areas of styrene polymerization and styrene monomer production. Styrene analysis of subcutaneous fat suggested that the monomer may have been present for as long as 3 d after exposure, a time when urinary metabolites and blood styrene were almost invariably undetectable. All three biological parameters were correlated with recency of exposure and estimated intensity of exposure within job categories.

Mortality experience of styrene-polystyrene polymerization workers. Initial findings.

A group of 560 individuals has been identified as employed on 1 May 1960 with at least five years seniority in a plant manufacturing styrene and polystyrene. In this plant workplace exposures included styrene, benzene and ethylbenzene, among other materials. All of the 560 individuals have been traced through 1975 and their vital status determined. Expected and observed deaths, by cause, were determined from 1 May 1960 or the tenth anniversary of employment in the plant through 31 December 1975. Over this relatively short period of time a deficit of deaths compared to that of the general population was observed (106.41 expected versus 83 observed). Among the 83 deaths, one was of leukemia, one of lymphoma and an additional death was accompanied by leukemia. A review of 361 additional death certificates revealed five additional cases of leukemia and four of lymphoma. The available information from the limited follow-up in time of the time of the cohort and from the randomly collected death certificates, while suggestive of a possible risk, is not definitive.

Survey of mortality among employees engaged in the manufacture of styrene and polystyrene at the BASF Ludwigshafen works.

A mortality survey of 1,960 employees currently or previously exposed to styrene at work has shown that the observed number of deaths from cancer or other causes is no higher than the number expected in the German population or in a group of BASF employees. Analyses of deaths occurring after a minimum period of five years in groups exposed for different durations (5 years, 10 years, 15 years, more than 15 years) indicated no increase in mortality with exposure time. This latter observation also applied to malignant tumors; therefore it may be inferred that prolonged exposure to styrene is not a cancer hazard.

Chromosome aberrations in lymphocytes of workers exposed to styrene.

Workers exposed to styrene in the reinforced plastics industry show a significant increase of chromosome aberrations, mainly chromosome breaks, in peripheral blood lymphocytes. The high incidence of aberrant lymphocytes (mean 15.1 +/- 4.8%; referents 2.0 +/- 1.3 %) was retained when the same men were reexamined one year later (mean 16.2 +/- 2.9 %). However, the frequency of sister chromatid exchanges (SCE), a newly developed sensitive parameter for the detection of recombinational exchanges linked with DNA repair, was not significantly increased (mean 5.3 +/- 1.0 SCE/cell) in comparison to the referents (mean 4.4 +/- 0.6 SCE/cell). This finding suggests a specific role of styrene or its metabolites in inducing genetic lesions mainly manifesting themselves as chromosomal breaks.

Exposure-response relationship between styrene exposure and central nervous functions.

For the study of the relationship between styrene exposure and symptoms and signs of central nervous dysfunctions, 98 male workers occupationally exposed to styrene were given clinical, neurophysiological and psychological examinations; also a symptom survey was made. Urinary mandelic acid concentrations, measured once a week during five consecutive weeks, were used to express the exposure intensity. Different unexposed groups were used for reference. No exposure-response relationship was observed between symptoms of ill health and the urinary mandelic acid concentration, although the exposed group as a whole expressed significantly more symptoms than the reference group. The occurrence of abnormal electroencephalograms was about 10% in the group of workers with mandelic acid concentrations below 700 mg/l, but it was 30% among those whose mandelic acid concentration exceeded 700 mg/l, a level corresponding to the 8-h time-weighted average (TWA) of styrene exposure of about 30 ppm. With regard to psychological functions, the first change in visuomotor accuracy became discernible when the urinary mandelic acid concentration exceeded 800 mg/l. A more pronounced decrement appeared in both visuomotor accuracy and psychomotor performance when the mandelic acid concentration exceeded 1,200 mg/l, which corresponds to an 8-h TWA of styrene exposure of about 55 ppm.

Mortality of styrene production, polymerization and processing workers at a site in northwest England.

The mortality of 622 men who worked for at least one year in the production, polymerization, and processing of styrene at a chemical site in the United Kingdom during the period 1945-1974 was surveyed up to the end of 1978; 3 072 male manual workers at the same site but unexposed to styrene were also studied. A statistically significant excess of lymphoma deaths was found in the exposed population, and two of the three deaths observed occurred in men less than 40 years of age. The small number of deaths and the lack of any evidence for an association with duration or level of exposure to styrene are reasons for interpreting this result cautiously. However, the otherwise normal pattern of mortality in the exposed population and the absence of any excess of lymphomas in the reference group lend some support to suggestions that exposure to styrene may be associated with lymphomas in man. An analysis of cancer registrations for the exposed population revealed no further cases of lymphoma but identified one case of lymphatic leukemia. An excess of laryngeal cancer registrations was found. As this effect has not been previously postulated and because of the small number of registrations, too much weight should not be attached to this one observation.

Morbidity among persons employed in styrene production, polymerization and processing plants.

BASF has been producing styrene and polystyrene since 1931. An investigation of morbidity was undertaken for 84 workers employed in the styrene plant and exposed for 1--36 years and 93 workers employed in the polystyrene plant and exposed for 1--38 years. In all groups the concentration of styrene in the atmosphere was measured at various points of the workplace. All workers underwent a thorough physical examination and also extensive laboratory tests, including the determination of urinary mandelic acid. The absenteeism and accident rates were also taken into consideration in both plants. Blood samples were also taken and mandelic acid tests made on a small group of 16 persons employed in polyester processing plants not attached to the BASF.

Some hygienic and clinical observations on styrene exposure.

Styrene exposure levels in the range of 100--300 ppm as an 8-h time-weighted average have been measured in small shops manufacturing glass fiber reinforced plastic products such as boats, steeping baths, etc. Exposure control through determinations of mandelic acid in the urine at the end of the workday has been found suitable and convenient. Over the years during the 1970s, there seems to have been amendments in the exposure situation in Sweden if judged from mandelic acid monitoring. More or less severe central nervous disturbances have been observed among the workers. Elevated levels of amino-transferases have been recorded but are of unclear long-term importance to liver function.

Styrene, its metabolism and the evaluation of hazards in industry.

The main products of styrene biotransformation excreted in human urine are mandelic and phenylglyoxylic acids. Phenylethylene oxide seems to be the first metabolite; this compound has been reported to be mutagenic and carcinogenic. The polarographic determination of mandelic acid has been used for about 20 years in Czechoslovakia as an exposure test for persons occupationally exposed to styrene. Only single cases of health damage have been reported to be due to styrene exposure during this time. Recently, however, elevated frequencies of chromosomal aberrations in peripheral lymphocytes have been observed in persons exposed to styrene in Czechoslovakia. The amount of phenylethylene oxide that can be formed in the human body during exposure to 50 ppm of styrene in air during a workshift is about 0.7 g. It would be hardly justifiable now to believe that styrene is not carcinogenic and mutagenic in man. The present Czechoslovakian maximum allowable concentration of styrene (200 mg/m3) should be reduced, and the concentration of 50 mg/m3 may be recommended as reasonable at this time. The corresponding biological limit value of mandelic acid might be 300 mg/l of urine from the last 2 h of the workshift.

Congenital malformations, mortality and styrene exposure.

The prevalence of congenital malformations among children born to styrene-exposed male and female workers, as well as the mortality of the exposed workers, was studied. A cohort of 2,209 workers (1,698 men, 511 women) was selected from the personnel files of 160 workplaces using styrene in the manufacture of reinforced plastic products. The earliest exposure histories began in 1960, but the majority of workers had been exposed after 1967. The data on children born to the exposed workers were linked with those of the Register of Congenital Malformations. The number of malformations of children born to the workers was, both before and during the styrene exposure, below the expected values. In the cohort there were 37 observed deaths (expected 74.0), six of which were due to cancer (expected 13.0). The cancer sites were the stomach (2 cases), bronchus (1), breast (1), ovary (1), and kidney (1 case). There were no cases of lymphatic or haematopoietic cancer. Most of the cancers appeared after short exposure times and soon after the commencement of exposure.

[Proposal for threshold limit values for organic solvent concentrations in alveolar air]. / Proposta di valori limite di concentrazione di solventi organici nell'aria alveolare.

The n-hexane concentration was determined in upper factory environmental air and in worker alveolar air. The relationship between the hexane alveolar concentration, and the hexane environmental concentration (Ca/Ci) was found to be steady during the 4,5 hours exposure and independent of the alveolar ventilation and hexane environmental concentration. These results suggest the hypothesis that alveolar TLV's can be fixed for hexane and other solvents.

[The effects of inhalation of styrene on the neurobehavior in the offsprings].

Pregnant Wistar rats were exposed to 0.60 +/- 18.9, 297.7 +/- 72.4 ppm styrene for 6 hours/day during 7 to 21 days of gestation. No significant differences among groups were found in the length of gestation or in the number of offspring delivered. Several neurobehavioral tests detected differences in the offspring exposed to styrene during gestation from controls. Even exposure to relatively low concentrations of styrene delayed some physiological developments, in addition to causing disturbances of the neuromotor coordination function (Rota-Rod performance) and learning acquisition (CRF). Furthermore, large dose led to subtle changes in emotional behavior and increases in spontaneous activities in addition to the delay of neurobehavioral developments.

[Possibility of studying morphofunctional characteristics of interglandular relations within the neuroendocrine system based on multifactorial analysis by the spline method]. / O vozmozhnosti morfofunktsional'noi kharakteristiki mezhzhelezistykh vzaimootnoshenii neiroendokrinnoi sistemy na osnove izucheniia mnozhestvennykh zavisimostei splain- metodom.

The possibility of morphofunctional characteristics of interglandular relations in the neuroendocrine system is shown by the study of non-linear multiple dependencies, by means of splines, of the effects of aromatic hydrocarbons. The method can be recommended for a total systems approach to the study of functional-morphological alterations of the adaptation processes and homeostasis normalization.