Gary M. Marsh

ORAL TETRAHYDROAMINOACRIDINE IN LONG-TERM TREATMENT OF SENILE DEMENTIA, ALZHEIMER TYPE

We treated 17 patients who had moderate to severe Alzheimers disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study. In the nonblinded first phase of the study, significant improvement occurred in subjects who received the drug, as compared with their pretreatment status, on the global assessment (P = 0.001), the Orientation Test (P = 0.001), and the more sophisticated Names Learning Test (P = 0.001). During the second phase, the subjects served as their own controls in a double-blind, placebo-controlled, cross-over study in which the order of administration of the drug and placebo was randomly assigned. Among the 14 subjects completing Phase II, THA treatment produced significantly better results than placebo on the global assessment (P = 0.003), the Orientation Test (P = 0.004), the Alzheimers Deficit Scale (P = 0.003), and the Names Learning Test (P = 0.001). Twelve subjects have entered Phase III, which involves long-term administration of oral THA. The average duration of treatment in these subjects at present is 12.6 months; symptomatic improvements have occurred, and no serious side effects attributable to THA have been observed. These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimers disease. We stress that further observations will be required before a clear assessment of the role of this agent can be made.

Aspartame: A Safety Evaluation Based on Current Use Levels, Regulations, and Toxicological and Epidemiological Studies

Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.

OCMAP-PLUS: a program for the comprehensive analysis of occupational cohort data.

The Occupational Cohort Mortality Analysis Program (OCMAP) has been redesigned for optimal microcomputer use and extended to include new computing algorithms. The new program, OCMAP-PLUS, offers a comprehensive, flexible, and efficient analysis of incidence or mortality rates and standardized measures in relation to multiple and diverse work history and exposure measures. New features include executable code, minimization of memory requirements, disk file storage of person-day arrays, stratified analyses by geographic area, employment status and up to eight exposure variables, a data imputation algorithm for study members with unknown race, and enhanced algorithms for constructing several time-dependent exposure measures. New modules create grouped data files for Poisson and logistic regression and risk set files for use in relative risk regression analysis. The Mortality and Population Data System (MPDS) provides external comparison rates and proportional mortalities. Analysis from two recent cohort mortality studies illustrate several new features.

Population attributable risk of aflatoxin-related liver cancer: Systematic review and meta-analysis ☆

BACKGROUND Over 4 billion people worldwide are exposed to dietary aflatoxins, which cause liver cancer (hepatocellular carcinoma, HCC) in humans. However, the population attributable risk (PAR) of aflatoxin-related HCC remains unclear. METHODS In our systematic review and meta-analysis of epidemiological studies, summary odds ratios (ORs) of aflatoxin-related HCC with 95% confidence intervals were calculated in HBV+ and HBV- individuals, as well as the general population. We calculated the PAR of aflatoxin-related HCC for each study as well as the combined studies, accounting for HBV status. RESULTS Seventeen studies with 1680 HCC cases and 3052 controls were identified from 479 articles. All eligible studies were conducted in China, Taiwan, or sub-Saharan Africa. The PAR of aflatoxin-related HCC was estimated at 17% (14-19%) overall, and higher in HBV+ (21%) than HBV- (8.8%) populations. If the one study that contributed most to heterogeneity in the analysis is excluded, the summarised OR of HCC with 95% CI is 73.0 (36.0-148.3) from the combined effects of aflatoxin and HBV, 11.3 (6.75-18.9) from HBV only and 6.37 (3.74-10.86) from aflatoxin only. The PAR of aflatoxin-related HCC increases to 23% (21-24%). The PAR has decreased over time in certain Taiwanese and Chinese populations. CONCLUSIONS In high exposure areas, aflatoxin multiplicatively interacts with HBV to induce HCC; reducing aflatoxin exposure to non-detectable levels could reduce HCC cases in high-risk areas by about 23%. The decreasing PAR of aflatoxin-related HCC reflects the benefits of public health interventions to reduce aflatoxin and HBV.

Cancers related to exposure to arsenic at a copper smelter.

OBJECTIVE--This is an update of an earlier study on the relation between exposure to arsenic in air and deaths from respiratory cancer. The purpose was to verify earlier findings of a supralinear dose response relation and to examine relations with other cancers, particularly those reported in studies on drinking water. METHODS--An earlier study of 2802 men who worked at a copper smelter for a year or more during the period 1940-64 and who were followed up for deaths during the period 1941-76 was updated until 1986. Estimates of exposure for the period 1977-1984 were added. RESULTS AND CONCLUSIONS--The additional follow up confirms the earlier finding that at low doses the increments in death rates for respiratory cancer for a given increment in dose are greater than at high doses. The additional follow up also shows significant increases in cancer of the large intestine and bone, and SMRs > 150 for cancer of the buccal cavity and pharynx, rectal cancer, and kidney cancer. There was a positive relation between exposure to arsenic in air and kidney and bone cancer, but none for the other cancers, except respiratory.

Mortality patterns among workers exposed to acrylamide: 1994 follow up.

OBJECTIVE: To update the mortality experience of a cohort of 8508 workers with potential exposure to acrylamide at three plants in the United States from 1984-94. METHODS: Analyses of standardised mortality ratios (SMR) with national and local rates and relative risk (RR) regression modelling were performed to assess site specific cancer risks by demographic and work history factors, and exposure indicators for acrylamide and muriatic acid. RESULTS: For the 1925-94 study period, excess and deficit overall mortality risks were found for cancer sites of interest: brain and other central nervous system (CNS) (SMR 0.65, 95% confidence interval (95% CI) 0.36 to 1.09), thyroid gland (SMR 2.11, 95% CI 0.44 to 6.17), testis and other male genital organs (SMR 0.28, 95% CI 0.01 to 1.59), and cancer of the respiratory system (SMR 1.10, 95% CI 0.99 to 1.22); however, none was significant or associated with exposure to acrylamide. A previously reported excess mortality risk of cancer of the respiratory system at one plant remained increased among workers with potential exposure to muriatic acid (RR 1.50, 95% CI 0.86 to 2.59), but was only slightly increased among workers exposed or unexposed to acrylamide. In an exploratory exposure-response analysis of rectal, oesophageal, pancreatic, and kidney cancer, we found increased SMRs for some categories of exposure to acrylamide, but little evidence of an exposure-response relation. A significant 2.26-fold risk (95% CI 1.03 to 4.29) was found for pancreatic cancer among workers with cumulative exposure to acrylamide > 0.30 mg/m3.years; however, no consistent exposure-response relations were detected with the exposure measures considered when RR regression models were adjusted for time since first exposure to acrylamide. CONCLUSION: The contribution of 1115 additional deaths and nearly 60,000 person-years over the 11 year follow up period corroborate the original cohort study findings of little evidence for a causal relation between exposure to acrylamide and mortality from any cancer sites, including those of initial interest. This is the most definitive study of the human carcinogenic potential of exposure to acrylamide conducted to date.

Mortality patterns among workers exposed to acrylamide

A cohort of 8854 men, 2293 of whom were exposed to acrylamide, was examined from 1925 to 1983 for mortality. This cohort consisted of four plant populations in two countries: the United States and The Netherlands. No statistically significant excess of all-cause or cause-specific mortality was found among acrylamide workers. Analysis by acrylamide exposure levels showed no trend of increased risk of mortality from several cancer sites. These results do not support the hypothesis that acrylamide is a human carcinogen.

RISING MORTALITY FROM MOTONEURON DISEASE IN THE USA, 1962-84

From 1962 to 1984, age-specific mortality for motoneuron disease (MND) in the United States rose in all demographic groups over the age of 40. The increase was seen in both men and women, and both whites and non-whites, and was most pronounced in the elderly (eg, 378% in white women aged 80-84 years). Men were at 50% higher risk than women, and whites had twice the risk of non-whites. These increases may reflect an improvement in case ascertainment, but they also seem to show a true rise in the incidence of MND, particularly among the elderly. Such an increase suggests an environmental aetiology.

Mortality among a cohort of US man-made mineral fiber workers: 1985 follow-up.

This 1983 to 1985 update of an earlier study examined the mortality experience of 16,661 man-made mineral fiber workers employed 1 year or more (6 months for two plants) during 1945 to 1963 (1940 to 1963 for one plant) at one or more of 17 US manufacturing plants. Using local death rates to estimate expected deaths there was a small statistically significant (P less than .05) excess in all malignant neoplasms (standardized mortality ratio [SMR] = 108.3) and in respiratory cancer (SMR = 112.1) for the total period 1946 to 1985. For respiratory cancer the excess was greatest for mineral wool workers. For glass wool workers and glass filament workers respiratory cancer SMR values were much lower. For workers exposed in the production of small-diameter fibers, the overall respiratory cancer SMR was slightly elevated but lower than in earlier reports. A total of four malignant mesotheliomas have now been noted on death certificates. Two of these were coded to the International Classification of Disease rubrics used to estimate 1.45 expected mesothelioma deaths for the total study. Overall, the evidence of a relationship between exposure to man-made mineral fibers and respiratory cancer appears to be somewhat weaker than in the previous update.

Historical cohort study of US man-made vitreous fiber production workers: I. 1992 fiberglass cohort follow-up: initial findings.

This 1986 to 1992 update and expansion of an earlier historical cohort study examined the 1946 to 1992 mortality experience of 32,110 workers employed for 1 year or more during 1945 to 1978 at any of 10 US fiberglass (FG) manufacturing plants. Included are (1) a new historical exposure reconstruction for respirable glass fibers and several co-exposures (arsenic, asbestos, asphalt, epoxy, formaldehyde, polycyclic aromatic hydrocarbons, phenolics, silica, styrene, and urea); and (2) a nested, matched case-control study of 631 respiratory system cancer (RSC) deaths in male workers during 1970 to 1992 with interview data on tobacco smoking history. Our findings to date from external comparisons based on standardized mortality ratios (SMRs) in the cohort study provide no evidence of excess mortality risk from all causes combined, all cancers combined, and non-malignant respiratory disease. Also, excluding RSC, we observed no evidence of excess mortality risk from any of the other cause-of-death categories considered. For RSC among the total cohort, we observed a 6% excess (P = 0.05) based on 874 deaths. Among long-term workers (5 or more years of employment) we observed a not statistically significant 3% excess based on 496 deaths. Among the total cohort, we observed increases in RSC SMRs with calendar time and time since first employment, but these were less pronounced among long-term workers. RSC SMRs were not related to duration of employment among the total cohort or long-term workers. In an externally controlled analysis of male workers at risk between 1970 and 1992, we observed no association between RSC SMRs and increasing exposure to respirable FG. Our findings to date from internal comparisons based on rate ratios in the case-control study of RSC were limited to analyses of categorized study variables with and without adjustment for smoking. On the basis of these analyses, the duration of exposure and cumulative exposure to respirable FG at the levels encountered at the study plants did not appear to be associated with an increased risk of RSC. RSC risk also did not seem to increase with time since first employment. There is some evidence of elevated RSC risk associated with non-baseline levels of average intensity of exposure to respirable glass, but when adjusted for smoking this was not statistically significant, and there was no apparent trend with increasing exposure. This same pattern of findings was observed for duration of exposure, cumulative exposure, and average intensity of exposure to formaldehyde. None of the other individual co-exposures encountered in the study plants appeared to be associated with an increased risk of RSC. The primary focus of ongoing analyses is to determine the extent to which our present findings are robust to alternative characterizations of exposure.