The Pliofilm cohort is the most intensely studied group of workers chronically exposed to benzene. Information on this cohort has been the basis for regulations and/or guidelines for occupational and environmental exposure to benzene. Rinsky et al. (1986, 1987) and Crump and Allen (1984) developed different approaches for reconstructing the exposure history of each member of the group. The predicted levels of exposure, combined with the data on the incidence of disease, have been used to estimate benzene's carcinogenic potency. In this paper, recent information from worker interviews and historical records from the National Archives and elsewhere were used to evaluate the accuracy of prior exposure estimates and to develop better ones for the cohort. The following factors were accounted for: (1) uptake of benzene due to short-term, high-level exposure to vapors, (2) uptake due to background concentrations in the manufacturing building, (3) uptake due to contact with the skin, (4) morbidity and mortality data on workers in the Pliofilm process, (5) the installation of industrial hygiene engineering controls, (6) extraordinarily long work weeks during the 1940s, (7) data indicating that airborne concentrations of benzene were underestimated due to inaccurate monitoring devices and the lack of adequate field calibration mated due to inaccurate monitoring devices and the lack of adequate field calibration of these devices, and (8) likely effectiveness of respirators and gloves. Our estimates suggest that Crump and Allen (1984) overestimated the exposure of workers in some job classifications and underestimated others, and that Rinsky et al. (1981, 1986) almost certainly underestimated the exposure of nearly all workers. Airborne concentrations of benzene at the St. Marys facility during the years of its operation were found (on average) to be about half those of the two Akron facilities. Our analysis indicates that short-term, high-level exposure to benzene vapors and dermal exposure significantly increased (by about 25-50%) the total absorbed dose of benzene for some workers. One of the key findings was that, unlike prior analyses, the three facilities probably had significantly different airborne concentrations of benzene, especially during the 1940s and 1950s.

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Acute and chronic exposure to benzene vapors poses a number of health hazards to humans. To evaluate the probability that a specific degree of exposure will produce an adverse effect, risk assessment methods must be used. This paper reviews much of the published information and evaluates the various risk assessments for benzene that have been conducted over the past 20 years. There is sufficient evidence that chronic exposure to relatively high concentrations of benzene can produce an increased incidence of acute myelogenous leukemia (AML). Some studies have indicated that benzene may cause other leukemias, but due to the inconsistency of results, the evidence is not conclusive. To predict the leukemogenic risk for humans exposed to much lower doses of benzene than those observed in most epidemiology studies, a model must be used. Although several models could yield plausible results, to date most risk assessments have used the linear-quadratic or conditional logistic models. These appear to be the most appropriate ones for providing the cancer risk for airborne concentrations of 1 ppb to 10 ppm, the range most often observed in the community and workplace. Of the seven major epidemiology studies that have been conducted, there is a consensus that the Pliofilm cohort (rubber workers) is the best one for estimating the cancer potency because it is the only one with good exposure and incidence of disease data. The current EPA, OSHA, and ACGIH cancer potency estimates for benzene are based largely on this cohort. A retrospective exposure assessment and an analysis of the incidence of disease in these workers were completed in 1991. All of these issues are discussed and the implications evaluated in this paper. The range of benzene exposures to which Americans are commonly exposed and the current regulatory criteria are also presented.

The electrophysiological properties of human coronary endothelial cells (HCEC) of macro- and microvascular origin were studied using the whole-cell configuration of the patch-clamp technique. The membrane potential of confluent HCEC (-41.9 +/- 3.9 mV (mean +/- SEM, n = 32) for macro- and -33.6 +/- 2.6 mV (n = 64) for microvascular cells, respectively) was less negative than the K+ equilibrium potential. Inward currents of isolated cells at potentials below the K+ equilibrium potential were blocked by external Ba2+ (1 mM), inactivated due to time- and voltage-dependent block caused by external Na+, and their amplitudes were enhanced by increasing extracellular [K+]; these currents were identified as inwardly rectifying K+ currents. Some isolated cells displayed outwardly directed K+ currents which were abolished after replacement of Cs+ for K+ on both sides of the membrane. Voltage-dependent Ca2+ currents could not be observed in isolated HCEC. Hyperpolarizations induced by vasoactive agonists have been observed in some endothelial cells from different species. In contrast, extracellularly applied ATP (adenosine-5'-triphosphate) and ADP (adenosine-5'-diphosphate) at micromolar concentrations depolarized confluent HCEC, whereas adenosine had no effect on resting potentials (RP), indicating that the nucleotide-induced depolarizations were mediated via P2- purinoceptors. These depolarizations occurred even after replacement of N-methyl-D-glucamine for extracellular Na+, indicating that Ca(2+)-influx was involved. There were no marked differences in the electrophysiological properties between cells of macro and microvascular origin.

Preclinical studies and testing strategies with and without the use of animal testing methods have the purpose of limiting risks whenever a new active substance is to be used as a medicinal product in humans. They should be designed in such a way as to achieve as early, risk-free, unproblematic, and economic a transition as possible from preclinical to clinical trials in medicinal products development. For this purpose the legitimate interests of subjects, patients, manufacturers (sponsors), and the scientific community as well as regulatory and competent authorities must be harmonized so as to achieve a course of action that is medicinally, ethically (also with respect to animal testing), and legally justified. The development of a new medicinal product is generally marked by a number of preclinical and clinical investigations; their sequential order with regard to contents and logic, the testing duration needed on an individual basis, and chronological overlaps when carrying out these studies are all to be determined. As every new active substance is a separate entity, investigations and testing strategies must be designed individually. The principle of flowcharts described in this text facilitates the development of a testing strategy adapted to a certain medicinal product by using decisiontree methods. At the same time, the flowchart principle allows for a structuring of the necessary scientific discussion between preclinical and clinical investigators as well as between sponsor and authorizing authority.