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The evaluation of iolgia markers is recoied as necsry to the future oftokcOy , epideniology, and q Iive risk assment. For bio cl nmrkes to becm widely accepted, their validity must be ascertained. This paper explores the range ofconsiderations that compose the concept of validiBt as it applies to the evaluation of bioogical markers. Three broad categories of validity (meaem ent, internal study, and external) are discussed in the context of evWaluating data for use inquantitative risk at. Frticular attention is given to the importnce ofmeuement validity in the consideration ofwhether to use biological markers in epidemiologic studies. The Three broad categories of validity can be distinguished: measurement validity, internal study validity, and external validity. Measurement validity has been defined as an expression ofthe degree to which ".. . a measurement measures what it purports to measure" (9). Internal study validity is the degree to which inferences drawn from a sample are warranted when account is taken of the study methods, the representativeness of the study sample, and the nature ofthe population from which the sample is drawn (9). External study validity is the extent to which the findings of a study can be generalized to other populations (9). likely that the risk assessments constructed from those measurements will also be invalid. Measurement validity characterizes the extent to which a marker ofa phenomenon has content validity (i.e., pertains to the underlying phenomenon); construct validity (i.e., correlates with other relevant characteristics of the underlying phenomenon); and criterion validity (i.e., predicts some component of the underlying phenomenon). In general, these three components ofmeasurement validity are best assessed in terms of the extent or degree to which they apply to the underlying phenomenon, rather than as an all-or-none condition (JO). Content ValidityContent validity is the extent to which a marker "incorporates the domain ofthe phenomenon under study" (9). For example, a marker of internal dose will have content validity if it reflects the dose contributed by all routes of exposure. A marker of effect will have content validity if it encompasses the essential characteristics of the disease it represents. In other words, the marker must pertain to the appropriate target organ, or its relationship to the natural history ofthe disease in question must be unambiguous. For example, a DNA adduct of benzo(a)pyrene (BaP) will have content validity as a marker of exposure in a study ofBaP-induced lung cancer, since the involvement ofDNA in BaP-induced carcinogenesis is well documented. In contrast, the development of DNA adducts in the N7 position might not have content validity as a marker of biologically effective dose ifthe 06 methylguanine adduct is shown to be that which is most clearly related to the carcnogenic process. However, the N7 adducts might be reasonably valid markers ofBaP biologically effective dose ifthe production of06 and N7 adducts are directly proportion...

Ethylene oxide (EtO) is a reactive epoxide and potent biocide. It is used widely in gas sterilization of hospital equipment. An estimated 75,000 health care workers in the United States have potential exposure. EtO binds covalently to deoxyribonucleic acid (DNA) and has been shown in 13 species to cause point mutations. Apparently, as a consequence of its alkylating ability, EtO exposure can result in chromosomal damage. In monkeys EtO exposure produces increased frequencies of sister chromatid exchanges (SCEs) and chromosomal aberrations. In man, five cytogenetic studies have shown dose-related increased frequencies of either SCE or chromosomal aberrations; in one study SCEs developed after regular exposures lasting less than five minutes per day. EtO is a reproductive toxin. In adult male rats, exposure produces decreased fertility, increased fetal deaths, and heritable chromosomal translocations. In pregnant female rats and rabbits, exposure causes increased fetal losses, and in one study in pregnant mice exposure was associated with increased numbers of malformed fetuses. In male monkeys EtO causes dose-related reductions in sperm count and sperm motility. In pregnant women, one study suggests that brief occupational exposure twice daily in concentrations of 20 ppm or above was associated with increased spontaneous abortions. EtO is carcinogenic to animals. In rats it causes dose-related increases in mononuclear cell leukemias, peritoneal mesotheliomas, and cerebral gliomas. In man, exposure has been associated in two epidemiologic studies with increased leukemias: 3 leukemias observed versus 0.2 expected in one study, and 2 observed versus 0.14 expected in the other; two additional small studies of limited power found no excess leukemias. Quantitative risk assessment indicates that from 634 to 1,093 excess deaths from cancer will occur per 10,000 workers exposed to EtO at 50 ppm over a working lifetime, and that 12 to 23 excess cancer deaths will occur per 10,000 workers exposed at 1 ppm. The National Institute for Occupational Safety and Health (NIOSH) recommends that EtO be regarded as a potential human carcinogen. NIOSH has recommended that eight-hour time-weighted average exposure to EtO be less than 0.1 ppm and that short-term peak exposure not exceed 5 ppm for more than ten minutes per working day.

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In January 1991, NIOSH completed a retrospective cohort mortality study of 3,588 Westinghouse Electric Corporation workers who had been engaged in the manufacture of electrical capacitors. The study evolved from a NIOSH Health Hazard Evaluation, which was conducted at the request of the Indiana State Board of Health because of its concern about PCB exposures among the Westinghouse workers. Life table analysis revealed a fourfold excess of deaths due to malignant melanoma. Though the workers were principally exposed to PCBs, the available exposure data did not lend itself to constructing an exposure-response curve that could relate PCB exposure to development of malignant melanomas. This was further complicated by the lack of substantial corroboration from other studies of PCB-exposed cohorts. Because of the magnitude of the malignant melanoma excess and the fact that malignant melanoma is probably more amenable to treatment and remediation than most other cancers, NIOSH determined that notification of the individual cohort members was a prudent and necessary public health action. This article describes the notification process from the time the decision to notify was made through the postnotification period. It details the interaction between NIOSH, the former and current plant owners, the two labor organizations that represented the workers at the plant, and the recipients of the notification materials. Scientific and other issues surrounding this notification effort are also discussed. A number of lessons were learned about the notification process; these are described for the benefit of others who conduct notifications.