Ischemic heart disease and spousal smoking in the National Mortality Followback Survey.

Data on never-smoking decedents from the 1986 National Mortality Followback Survey were used to perform a case-control analysis of ischemic heart disease in relation to spousal cigarette smoking. The case groups consisted of 475 men and 914 women who died from heart disease. Controls consisted of 998 men and 1930 women who died from other causes. In this study there was no association between spousal smoking and ischemic heart disease in either sex (males, odds ratio = 0.97; females, odds ratio = 0.99). The results of this study are in striking disagreement with risk elevations reported in several previous studies of spousal smoking and heart disease.

Publication bias in the environmental tobacco smoke/coronary heart disease epidemiologic literature.

Two approaches are used to assess publication bias in the environmental tobacco smoke/coronary heart disease (ETS/CHD) literature: (1) Statistical tests applied to all sex-specific relative risk (rr) estimates from 14 previously published studies indicate that publication bias is likely. A funnel graph of the studies' log relative risks plotted against their standard errors is asymmetrical, and weighted regression of the studies' log relative risks on their standard errors is significant (P < 0.01). (2) Previously unpublished ETS/CHD relative risks from the American Cancer Society's Cancer Prevention Studies (CPS-I and CPS-II) and the National Mortality Followback Survey (NMFS) do not show an increased CHD risk associated with ETS exposure. CPS-I: men, rr = 0.97 (0.90-1.05); CPS-I: women, rr = 1.03 (0.98-1.08); CPS-II: men, rr = 0.97 (0.87-1.08); CPS-II: women, rr = 1.00, (0.88-1.14); NMFS: men, rr = 0.97 (0.73-1.28); women, rr = 0.99 (0.84-1.16). Comparison of pooled relative risk estimates from 14 previously published studies (rr = 1.29; 1.18-1.41) and unpublished results from three studies (rr = 1.00; 0.97-1.04) also indicates that published data overestimate the association of spousal smoking and CHD (chi 2 = 25.1; P < 0.0001).

Inconsistency between workplace and spousal studies of environmental tobacco smoke and lung cancer.

In a risk assessment released at the end of 1992, the U.S. Environmental Protection Agency (EPA) concluded that environmental tobacco smoke (ETS) is a known human lung carcinogen. The Agency reached that conclusion primarily on the basis of epidemiologic studies of self-reported never-smoking women, in which the exposure index was marriage to a smoker. However, the use of the spousal smoking exposure surrogate introduces many potential confounding factors. Such confounding and bias due to denial of active smoking are likely explanations for weak and inconsistent reported ETS-lung cancer associations. This contention is supported by the results of 14 worldwide studies of lung cancer and ETS exposure in the workplace, which in combination indicated no risk elevation. Workplace ETS-lung cancer studies are not subject to the bias and confounding introduced by the spousal smoking exposure surrogate. The EPA ignored the workplace studies in its risk assessment and extrapolated the results of spousal smoking studies to workplace and other sources of ETS exposure. In its estimate of ETS-attributable lung cancer deaths in the United States, the EPA ascribed over 70% of the deaths to nonspousal ETS exposure, primarily workplace exposure. Considered in their entirety, the ETS-lung cancer epidemiologic data do not support a causal inference or provide a scientific basis for government regulation of smoking in the workplace.

Risk assessment of 2,3,7,8-TCDD using a biologically based cancer model: a reevaluation of the Kociba et al. bioassay using 1978 and 1990 histopathology criteria.

The Moolgavkar-Venzon-Knudson (M-V-K) two-stage model for carcinogenesis was used to estimate the risk-specific dose (RsD) based on the incidence of tumors reported by Kociba et al. (1978) for Sprague-Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; dioxin). The results from the recently completed (1990) reevaluation of the Kociba et al. study, which used the current National Toxicology Program (NTP) pathology criteria, were also evaluated. Time-to-tumor information for each rat was incorporated into the analysis. Model parameters for the approximate form of the hazard function of the two-stage M-V-K model were determined by maximum likelihood estimation. This simplification was significant but necessary, because laboratory data on the intermediate cell growth rate and the transition rates have not been determined. Estimates of the RsD (10(-6) risk) (based on the original 1978 histopathology results) were 10 fg/kg/d when carcinomas and hyperplastic nodules were combined and 150 fg/kg/d when only carcinomas were considered. In contrast, using the 1990 histopathology data, the RsD (10(-6) risk) was 80 fg/kg/d when adenomas and carcinomas were combined and 25,000 fg/kg/d when only hepatocellular carcinomas were considered. Since the two-stage M-V-K model is intended to predict the occurrence of malignant tumors, the mathematically appropriate RsD is 25,000 fg/kg/d (10(-6) risk). Because the model does not account for pharmacokinetics or the possibility of other toxic effects, the appropriate RsD (10(-6) risk) for humans should be much smaller. Using the carcinoma data only, a sensitivity analysis of key parameters in the model was conducted. Results indicated that the ranges of plausible values for the RsD (10(-6) risk) for the original 1978 and the 1990 reevaluation data were 70-2600 fg/kg/d and 120-50,000 fg/kg/d, respectively. The lowest plausible RsD is, therefore, approximately 10-fold greater than the current U.S. EPA RsD (10(-6) risk) of 6.4 fg/kg/d [which is based on the linearized multistage (LMS) model]. Even though these results must be considered preliminary until some of the values for the model parameters are experimentally determined and a complete physiologically based or receptor-based model is developed, this analysis shows that nearly any plausible laboratory data on tumor progression will yield a much higher RsD than currently embraced by the U.S. EPA.

Risk factors for doxorubicin-induced congestive heart failure.

Potential risk factors responsible for development of doxorubicin-induced congestive heart failure were examined through retrospective analysis of 4018 patient records. The overall incidence of drug-induced congestive heart failure was 2.2% (88 cases). The probability of incurring doxorubicin-induced congestive heart failure was related to the total dose of doxorubicin administered. There was a continuum of increasing risk as the cumulative amount of administered drug increased. A weekly dose schedule of doxorubicin was associated with a significantly lower incidence of congestive heart failure than was the usually employed every 3-week schedule. An increase in drug-related congestive heart failure was also seen with advancing patient age. Performance status, sex, race, and tumor type were not risk factors. These data will enable clinicians to better estimate the risk/benefit ratio in individual patients receiving prolonged administration of doxorubicin. They also provide a basis for the investigation of less cardiotoxic anthracycline analogues or for designing measures to prevent doxorubicin-induced cardiomyopathy.

Analysis of oncornavirus RNA subunits by electron microscopy.

Subunits of oncornavirus (avian myeloblastosis virus) RNA were isolated from purified 60--70S viral RNA by heat dissociation. Molecules sedimenting at 35 S, assumed to be the major component of the viral genome, were visualized in the electron microscope and their lengths were statistically analyzed. The results indicate a rather heterogeneous population of molecules with five distinct, reproducible size groups, an observation that excludes the assumption of random degradation of the genome. In addition, molecules of 28 and 18S RNA, always present in oncornavirus RNA preparations, were examined with the same methods. Some of these molecules possess secondary-structure regions similar to those characteristic for ribosomal RNA.