Surrogate studies, exposure

As with some of the chronic animal studies, exposures in most of the occupational miner cohorts consist of exposure to radon and radon progeny in the presence of other contaminants such as uranium ore dust, diesel-engine exhaust, or other mine pollutants. Only a few studies of lung cancer associated with environmental exposures to radon and radon daughters have been reported. These studies are primarily case-control or case-referent studies that involve a small number of subjects and have exposure estimates that are based on either surrogates for measurements or limited measurements. Additional studies of the extent of the hazard associated with environmental radon daughter exposures would provide useful information since radon is an ubiquitous substance, especially as they compare to estimates of the human health hazard based on the occupational setting. 

FACTORS IN CHOOSING APPROPRIATE SURROGATE STUDIES FOR EXPOSURE ASSESSMENTS ... 

Studies in indoor environments of dermal contact transfer required an estimate, and a tight-fitting whole-body dosimeter was adopted and initially considered as a surrogate for skin (Krieger et al., 2000). Contact with treated surfaces was limited to feet, hands, limbs, and torso. Standardized Jazzercize to represent daily human activities and maximum contact was incorporated into protocols for indoor exposure studies (Ross et al., 1990,1991). Comparative studies will be reported elsewhere (Krieger et al., 2000). 

However, the number of studies that can be performed in humans is limited by both ethical (unnecessary exposure of human volunteers to risks) and economical factors. Therefore, in vitro testing may be invoked as a surrogate of the surrogate provided that a linear relationship between relevant in vivo and in vitro exists, i.e., an IVIVC. 

Exposure-response data, using short-term biomarkers or surrogate endpoints, can sometimes make further exposure-response studies from clinical endpoints xmnecessary. For example, if it can be shown that the short-term effect does not increase beyond a particular dose or concentration, there may be no reason to explore higher doses or concentrations in the clinical trials. Similarly, short-term exposure-response studies with biomarkers might be used to evaluate early (i.e., first dose) responses seen in clinical trials. 

Detection bias occurs in convenience-cohort studies when any measure of substance exposure is correlated with differences in medical scrutiny. For example, the positive relationship between reser-pine (a blood pressure medication) and breast cancer might be attributable to the fact that women under treatment for high blood pressure are more likely to have breast exams, which detect otherwise silent breast cancers (Feinstein 1988, 1261). The same might be true of the relationship between alcohol intake and breast cancer, because alcohol could be a surrogate for income and more frequent breast cancer screening and mammography (Feinstein 1988, 1261). 

Figure 11.6 illustrates a process to follow to assess a substance s absorption potential. The first step is to establish the types of individuals (i.e., workers, consumers, or general population) at greatest risk of exposure and the known or likely routes (dermal, inhalation, or oral) by which exposure will take place. The second step is to determine whether measured absorption data for the substance are available. Such data are often not available, but animal absorption data can be used as surrogates for human data in many cases. If no measured absorption data are available, toxicity data from studies involving humans or animals exposed to the substance may be useful. For example, if systemic toxic effects were noted in humans or animals following dermal (or oral or inhalation) exposure to a substance, especially at low doses, then obviously the substance is absorbed via this route. 

A number of studies have examined pregnancy outcomes following paternal exposure or paternal and maternal exposure to 2,3,7,8-TCDD. No significant alterations in the incidence of spontaneous abortions were found in several studies of Vietnam veterans. In a case-control study conducted by Aschengrau and Monson (1989), no association was observed between paternal military service in Vietnam and the risk of spontaneous abortion (odds ratio [OR] of 0.88, 95% confidence interval [Cl] of 0.42-1.86). A limitation of this study is that service in Vietnam is not an adequate exposure surrogate for 2,3,7,8-TCDD exposure ... 

---