Positive findings

Figure 3.22 shows, in bloek diagram form, the transfer funetions for a resistanee thermometer and a valve eonneeted together. The input X[ t) is temperature and the output Xo t) is valve position. Find an expression for the unit step response funetion when there are zero initial eonditions. 

Male mice exposed to 7.3 mg/kg/day for 13 weeks had significantly decreased spleen weights and decreased neutrophil counts (Hoechst 1984b), indicating that immune activity in mice may also be affected. An intermediate-duration oral MRL of 0.005 mg/kg/day was derived based on the NOAEL of 0.45 mg/kg/day for immunotoxicity identified in the Banerjee and Hussain (1986) study. In support of these positive findings, Khurana et al. (1998) observed decreased macrophage functionality, in the absence of any other apparent toxicological effects, in 1-day-old broiler chicks fed 30 ppm endosulfan in the diet for 4 or 8 weeks. 

Ensure that the analytical methodology gives reliable results in terms of identity (absence of false-positive findings) and of absence (no false-negative findings) of the analyte(s). This requires processing of concurrent analytical quality control samples. 

The ACC/AHA recommends that P-blockers be initiated in all patients with NYHA FC I to IV or ACC/AHA stages B through D heart failure if clinically stable.1 To date, only three p-blockers have been shown to reduce mortality in systolic HF, including the selective prantagonists bisoprolol and metoprolol succinate, and the non-selective pr, p2-, and arantagonist carvedilol.29 33 The positive findings should not be extrapolated to be indicative of a class effect, as bucindolol did not exhibit a beneficial effect on mortality when studied for HF, and there is limited information with propranolol and atenolol. 

Despite these positive findings, results from inhibitor studies are controversial. Thus, sulphobromophthalein, a known inhibitor of glutathione-S-transferase [42] has been reported both to inhibit [43] and not to inhibit [44—47] vasorelaxation by GTN, while other findings [48] favored involvement of the enzyme in GTN metabolism of cultured smooth muscle cells. 

To relate a positive finding in an in vitro test to the in vivo situation, one must either compare the concentration that caused the positive developmental effect in vitro to the exposure level of the embryo in vivo or compare the in vitro concentration for a developmental effect to the matemotoxicity that would be associated with exposure at that concentration in vivo. To do the necessary pharmacokinetic studies in vivo would defeat the purpose of using an in vitro test. It would be very desirable and may be possible, though, to have an endpoint in an in vitro test that would correlate with maternal toxicity. 

In vitro developmental toxicity systems have clearly been usefid for studies of mechanisms of developmental effects (e.g., Datson et al., 1989) — use (3) in the list above. It is unclear, though, whether in vitro developmental toxicity tests will provide useful information about developmental toxicity that is not derived from whole animal studies [use (4) from the list]. As is true for a possible use as a prescreen, the interpretation of a positive finding in an in vitro test will depend on knowing the exposure level in vivo. When this is known, the in vitro information could be helpful. The results of in vivo studies, though, would still likely be considered definitive for that species. 

A method proposed by Schweder and Spjotvoll (1982) is based on a plot of the cumulative distribution of observed p values. Farrar and Crump (1988) have published a statistical procedure designed not only to control the probability of false positive findings, but also to combine the probabilities of a carcinogenic effect across tumor sites, sexes, and species. 

Examining the chromosomes of some of our volunteers before and after LSD exposure turned up no significant changes. Nevertheless, reports both of chromosome breakage and non-breakage continued until an almost equal number of negative and positive findings had accumulated in about 40 scientific articles. 

Animal data are available for intermediate exposures by the inhalation and dermal routes of exposure. No animal data were located by the oral route. Most of these studies found no evidence of toxicity in any of the exposure conditions used in each (Carpenter et al. 1976 Bruner 1984 Lock et al. 1984 NTP/NIH 1986). However, the lack of toxicity in these studies has not been verified by more than one study using the same fuel oil, species, and/or route of exposure. In one aerosol inhalation study (Dalbey et al. 1987) there were positive findings for respiratory, hematological, and body weight effects at higher doses than those used in the studies by Carpenter et al. (vapor) (1979) and Lock et al. (aerosol) (1984). However, MRLs cannot be derived from these data because the Dalbey et al. study was not designed to test for a dose-response relationship, and therefore, the exact LOAEL(s) could not be determined for these effects. 

In another aerosol study with positive findings, only one concentration level was tested (Noa and ninait 1987a). 

---