Use of short term test systems for the prediction of the hazard represented by potential chemical carcinogens

It has been hypothesized that results from the short term bioassays will ultimately provide information that will be useful for human health hazard assessment. Although toxicologic test systems have become increasingly refined, to date, no investigator has been able to provide qualitative or quantitative methods which would support the use of short term tests in this capacity.^ Historically, the validity of the short term tests have been assessed using the framework of the epidemiologic/medical screens. In this context, the results of the carcinogen (long term) bioassay is generally used as the standard. However, this approach is widely recognized as being biased and, because it employs qualitative data, cannot be used in the setting of priorities. In contrast, the goal of this research was to address the problem of evaluating the utility of the short term tests for hazard assessment using an alternative method of investigation.^ Chemical carcinogens were selected from the list of carcinogens published by the International Agency for Research on Carcinogens (IARC). Tumorigenicity and mutagenicity data on fifty-two chemicals were obtained from the Registry of Toxic Effects of Chemical Substances (RTECS) and were analyzed using a relative potency approach. The relative potency framework allows for the standardization of data "relative" to a reference compound. To avoid any bias associated with the choice of the reference compound, fourteen different compounds were used.^ The data were evaluated in a format which allowed for a comparison of the ranking of the mutagenic relative potencies of the compounds (as estimated using short term data) vs. the ranking of the tumorigenic relative potencies (as estimated from the chronic bioassays). The results were statistically significant (p $<$.05) for data standardized to thirteen of the fourteen reference compounds. Although this was a preliminary investigation, it offers evidence that the short term test systems may be of utility in ranking the hazards represented by chemicals which may be human carcinogens. ^

Effects of informative censoring on the hazard function: Application to the proportional hazards regression model

The standard analyses of survival data involve the assumption that survival and censoring are independent. When censoring and survival are related, the phenomenon is known as informative censoring. This paper examines the effects of an informative censoring assumption on the hazard function and the estimated hazard ratio provided by the Cox model.^ The limiting factor in all analyses of informative censoring is the problem of non-identifiability. Non-identifiability implies that it is impossible to distinguish a situation in which censoring and death are independent from one in which there is dependence. However, it is possible that informative censoring occurs. Examination of the literature indicates how others have approached the problem and covers the relevant theoretical background.^ Three models are examined in detail. The first model uses conditionally independent marginal hazards to obtain the unconditional survival function and hazards. The second model is based on the Gumbel Type A method for combining independent marginal distributions into bivariate distributions using a dependency parameter. Finally, a formulation based on a compartmental model is presented and its results described. For the latter two approaches, the resulting hazard is used in the Cox model in a simulation study.^ The unconditional survival distribution formed from the first model involves dependency, but the crude hazard resulting from this unconditional distribution is identical to the marginal hazard, and inferences based on the hazard are valid. The hazard ratios formed from two distributions following the Gumbel Type A model are biased by a factor dependent on the amount of censoring in the two populations and the strength of the dependency of death and censoring in the two populations. The Cox model estimates this biased hazard ratio. In general, the hazard resulting from the compartmental model is not constant, even if the individual marginal hazards are constant, unless censoring is non-informative. The hazard ratio tends to a specific limit.^ Methods of evaluating situations in which informative censoring is present are described, and the relative utility of the three models examined is discussed. ^

Seismic properties of sheeted dikes from ODP Hole 111-504B

Seismic velocities have been measured at confining pressures to 600 MPa for eight samples of sheeted dike rock obtained from Hole 504B during Leg ODP 111. The compressional- and shear-wave velocities are, in general, higher than the velocities measured in overlying dike rocks obtained from the hole during DSDP Leg 83. The velocity gradients observed in Layer 2C result from decreasing porosity with depth and increasing metamorphic grade. The laboratory-measured velocities of the Leg 111 dike rocks are similar to those of dike rocks reported for the Bay of Islands, Samail, and Troodos ophiolites.

Seismic properties of volcanic rocks from DSDP Hole 62-465A

Hess Rise, a major structural feature in the northern Pacific, is one of several oceanic plateaus which apparently possess anomalous seismic structures (Sutton et al., 1971). Hence, Laboratory measurements of compressional- and shear-wave velocities in rocks from oceanic plateau regions are of considerable interest. Several questions come to mind: (1) Are compressional - wave velocities of volcanic rocks from oceanic plateaus similar to basalts of equivalent age from normal oceanic crust? (2) Do velocity-density relations for plateau rocks fit the well-established trends for Layer 2 basalts? (3) How do Poisson's ratios, determined from compressional- and shear-wave velocities, of oceanic plateau rocks compare with those of normal sea-floor basalts? To answer these questions, we have selected for velocity measurements five volcanic samples from different depths from Hole 465A, on southern Hess Rise. It is particularly significant that all the rocks are vesicular and have been highly altered, which significantly affects their elastic properties.