Monitoring human tissues for toxic substances: a follow-up to the National Academy of Sciences (NAS) report.

In 1991, the National Academy of Sciences (NAS) published a report, Monitoring Human Tissues for Toxic Substances, which presented a summary of thinking about the banking of human tissue specimens at the time the report was completed. The present article summarizes the findings and recommendations in the NAS report. Events have moved very rapidly since that time, but some history may be helpful in understanding how we have come to where we are today.

Identification of persons with cardiorespiratory conditions who are at risk of dying from the acute effects of ambient air particles.

This study was undertaken to identify subgroups of the population susceptible to the effects of ambient air particles. Fixed-site air pollution monitors in Montreal, Quebec, Canada, provided daily mean levels of various measures of particulates and gaseous pollutants. Total sulfates were also measured daily (1986-1993) at a monitoring station 150 km southeast of the city (Sutton, Quebec, Canada). We used coefficient of haze (COH), extinction coefficient, and Sutton sulfates to predict fine particles and sulfates from a fine particles model for days that were missing. We used the universal Quebec medicare system to obtain billings and prescriptions for each Montreal resident who died in the city from 1984 to 1993. These data were then used to define cardiovascular and respiratory conditions that subjects had before death. Using standard Poisson regression time-series analyses, we estimated the association between daily nonaccidental mortality and daily concentrations of particles in the ambient air among persons with cardiovascular and respiratory conditions diagnosed before death. We found no persuasive evidence that daily mortality increased when ambient air particles were elevated for subgroups of persons with chronic upper respiratory diseases, airways disease, cerebrovascular diseases, acute coronary artery disease, and hypertension. However, we found that daily mortality increased linearly as concentrations of particles increased for persons who had acute lower respiratory diseases, chronic coronary artery diseases (especially in the elderly), and congestive heart failure. For this latter set of conditions, the mean percent increase in daily mortality (MPC) for an increase in the COH across its interquartile range (18.5 COH units per 327.8 linear meters), averaged over the day of death and the 2 preceding days, was MPC = 5.09% [95% confidence interval (CI) 2.47-7.79%], MPC = 2.62 (95% CI 0.53-4.75%), and MPC = 4.99 (95% CI 2.44-7.60%), respectively. Adjustments for gaseous pollutants generally attenuated these associations, although the general pattern of increased daily mortality remained. In addition, there appeared to be a stronger association in the summer season. The positive associations found for persons who had acute lower respiratory diseases and congestive heart failure are consistent with some prevailing hypotheses and may also be consistent with recent toxicologic data implicating endothelins. Further epidemiologic studies are required to confirm these findings.

The practice of meta-analysis.

Meta-analysis seems to have a potentially useful role in carefully selected situations where the primary literature is of good quality, heterogeneity in the response to treatment of the tested population is small and well-understood, interest centers on estimation of a specific, critical parameter of outcome, and the meta-analyst is deeply expert in the subject matter. Other uses can produce, and have produced, results that may be seriously misleading. Five short case studies are presented (diethylstilbestrol and outcome of pregnancy, chlorination of drinking water and cancer, cisplatin and cancer of the ovary, antibiotic therapy for otitis media with effusion, and beta-agonists and asthma).

Qualitative assessment of studies included in a meta-analysis: DES and the risk of pregnancy loss.

Meta-analysis, the qualitative and quantitative integration of available research information, is increasingly used in clinical research. This report examines the qualitative elements of meta-analysis through critical review of two published examples that assessed the effect of diethylstilboestrol (DES) on miscarriage and neonatal mortality, respectively. Our subjective review showed the internal validity of three of five trials aggregated in the former meta-analysis to be severely compromised. The remaining two trials (data from which were aggregated in the latter meta-analysis), while internally valid, studied different clinical populations. Therefore, pooling of their results may have been clinically inappropriate. In conclusion, meta-analysis involves substantial elements of subjective judgment. Qualitative assessment of studies is of pivotal importance, because the validity of any summary estimate of effect hinges on both the methodologic quality and the combinability of the aggregated studies.

Risk assessment--the mother of all uncertainties. Disciplinary perspectives on uncertainty in risk assessment.

Uncertainty in the detection and evaluation of chemical hazards to health leads to challenges when conducting risk assessments. Some of the uncertainty has to do with data, some with incomplete understanding of processes, and some with the most fundamental ways of viewing the questions. True variability--across space, in time, or among individuals--complicates the search for understanding many important aspects of risk. A few statistical and toxicologic tools are available to assess uncertainty. Three methods of classifying uncertainty are briefly discussed. In addition, our disciplinary background may influence how we view and discuss variability and uncertainty. We rarely know as much as we think we do (and not just in risk assessment). Great uncertainty is likely to remain an important part of risk assessment for some decades to come.

Identifying subgroups of the general population that may be susceptible to short-term increases in particulate air pollution: a time-series study in Montreal, Quebec.

This study was undertaken in order to shed light on which groups of the general population may be susceptible to the effects of ambient particles. The objectives of the study were (1) to determine whether concentrations of particles in the ambient air of Montreal, Quebec, were associated with daily all-cause and cause-specific mortality in the period 1984 to 1993, and (2) to determine whether groups of the population had higher than average risks of death from exposure to particles. From the network of fixed-site air pollution monitors in Montreal we obtained daily mean levels of various measures of particles, gaseous pollutants, and weather variables measured at Dorval International Airport. We also used measurements of sulfate from an acid rain monitoring station 150 km southeast of the city (Sutton, Quebec). We estimated associations for particulate matter (PM) with an aerodynamic diameter of 10 microns or smaller (PM10), or 2.5 microns or smaller (PM2.5), total suspended particles (TSP), coefficient of haze (COH), an extinction coefficient, and sulfate. Because substantial data for fine particles were missing, we developed a regression model to predict PM2.5 and to predict sulfate from PM2.5. In the main body of the report, we present results for COH, predicted PM2.5, and sulfate. Detailed results for all pollutants are included in Appendices H through O, which are available on request from Health Effects Institute and from the HEI web site at www.healtheffects.org. To address the first objective, we made use of the underlying causes of death among all 140,939 residents of Montreal who died between 1984 and 1993. We regressed the logarithm of daily counts of cause-specific mortality on the daily mean levels for a variety of measures of particles, accounting for seasonal and subseasonal fluctuations in the mortality time series, overdispersion, and weather factors. To address the second objective, we developed algorithms to define conditions that subjects had prior to death, with the focus on cardiopulmonary diseases. These algorithms were based on information retained on the databases of the universal Quebec Health Insurance Plan (QHIP). The databases include records of all procedures (e.g., type of surgery), physician visits, and consultations carried out by all physicians in Quebec. For persons > or = 65 years and for all recipients of social assistance the prescription database contains records of all pharmaceuticals dispensed (type of medication, dose, quantity). For each group of conditions defined, we used the same statistical model that was used in the analyses of all nonaccidental causes of death. In the analyses of cause-specific mortality, we found evidence of associations for all nonaccidental causes of death and specific causes of death--cancer, coronary artery disease, respiratory diseases, and diabetes--that were consistent across most metrics of ambient air particle concentrations, evaluated as the 3-day mean of particle concentrations measured on the day of death (lag 0) and on each of the two days before death (lag 1, lag 2). Associations for all cardiovascular diseases combined were found only with sulfate. As well, we generally found increased daily mortality for persons 65 years of age and over. The results for all nonaccidental causes of death are similar to findings from other studies; the mean percent increase in mortality for a 100 micrograms/m3 increase in daily TSP at lag 0 was 6.7%. In the analyses of the groups defined from the QHIP data, there was little evidence of associations with air pollutants among persons who before death were classified as having acute or chronic upper respiratory diseases, airways diseases, hypertension, acute coronary artery diseases, and cerebrovascular diseases. On the other hand, we found consistent increases across most types of ambient particles for persons who had cancer, acute lower respiratory diseases, any form of cardiovascular disease, chronic coronary artery diseases, and congestive heart failure. As well, we found an association for individuals who did not have any cardiovascular disease, lower respiratory diseases, and cancer. This latter group consisted of persons who had no interactions with the health care system one year before death (12%) and individuals with a wide variety of potentially fatal diseases (52%), including neurological conditions (12%), diabetes (8%), cardiac dysrhythmias (8%), dementia (6%), organic psychotic disorders (6%), and anemias (4%). As statistical power was reduced in the analyses presented above, differences between groups (e.g., < 65 and > or = 65 year age groups) were not usually statistically significant. The association with diabetes has not been reported previously, and this needs to be replicated in other studies. (ABSTRACT TRUNCATED)

Trends in cancer mortality: perspectives from Italy and the United States.

Cancer continues to be a major public health problem in Italy, as it is throughout the world. We analyzed age-adjusted mortality rates for all cancers combined and for specific cancer sites in Italy for five year periods from 1950 to 1989. We compared trends in Italian cancer mortality to those observed in the United States during the same time period. We also considered some ancillary data including age-specific mortality rates, as well as incidence and five year relative survival data from the Modena Province. Age-adjusted cancer mortality rates in Italy are increasing in males and, to a lesser extent, females. This finding is in contrast to a recent plateau in age-adjusted cancer mortality rates in the United States. In Italy, stomach cancer mortality has declined substantially, counteracting marked increases in lung cancer mortality, particularly in males, and breast and lung cancer in females. Changes in cancer mortality in Italy, as in the US, have been driven primarily by changes in disease incidence rather than advances in therapeutics. These data suggest a need for realignment of cancer control resources toward prevention, particularly with regard to lung cancer and tobacco usage.