Annulation of Conjugated Azine-Imine with a Sulfoxonium Ylide in a Noncarbenoid Route to Synthesize Multisubstituted Imidazole-Fused Heterocycles.

A new [4+1]-annulation of in situ generated heterocyclic azine-aldimines with ß-keto sulfoxonium ylides has been developed. The reaction constructs N-fused imidazole rings. In the reaction, the ylides play a dual-functional role of a nucleophilic 1,1-dipolar one-carbon synthon and a source of an internal oxidant, dimethyl sulfoxide, that promotes in situ dehydrogenation to product scaffolds. The method enables access to imidazo-pyridine, pyrazine, and pyrimidine heteroaromatics.

Relationship between insulin sensitivity and insulin secretion rate: not necessarily hyperbolic.

AIMS: There is general acceptance that the physiological relationship between insulin sensitivity and insulin secretion is hyperbolic. This conclusion has evolved from studies in which one test assessed both variables, and changes in plasma insulin concentration were used as a surrogate measure for insulin secretion rate. The aim of this study was to see if a hyperbolic relationship would also emerge when separate and direct measures were used to quantify both insulin sensitivity and insulin secretion rate. METHODS: Steady-state plasma glucose (SSPG) was determined in 146 individuals without diabetes using the insulin suppression test, with 1/SSPG used to quantify insulin sensitivity. The graded-glucose infusion test was used to quantify insulin secretion rate. Plasma glucose and insulin concentrations obtained during an oral glucose tolerance test (OGTT) were used to calculate surrogate estimates of insulin action and insulin secretion rate. A hyperbolic relationship was assumed if the ß coefficient was near -1 using the following model: log (insulin secretion measure) = constant + ß × log (insulin sensitivity measure). RESULTS: OGTT calculations of insulin sensitivity (Matsuda) and plasma insulin response [ratio of insulin/glucose area-under-the-curve (AUC) or insulin total AUC] provided the expected hyperbolic relationship [ß = -0.95, 95% CI (-1.09, -0.82); -1.06 (-1.14, -0.98)]. Direct measurements of insulin sensitivity and insulin secretion rate did not yield the same curvilinear relationship [ß = -1.97 (-3.19, -1.36)]. CONCLUSIONS: These findings demonstrate that the physiological relationship between insulin sensitivity and insulin secretion rate is not necessarily hyperbolic, but will vary with the method(s) by which it is determined.

Nonlinearity in the lung cancer dose-response for airborne arsenic: apparent confounding by year of hire in evaluating lung cancer risks from arsenic exposure in Tacoma smelter workers.

Most analytic studies of human epidemiologic data have affirmed the linear association between excess lung cancer risk and airborne arsenic exposure. Recent Canadian analyses, however, based on the mortality follow-up of Tacoma smelter workers from 1940-1976, provided strong evidence of a nonlinear dose-response when lung cancer risk was expressed in terms of the standardized mortality ratio. Using recently updated data covering ten additional years of mortality experience among Tacoma workers (1940-1986), new analyses were undertaken to further explore nonlinearity in the lung cancer dose-response in this worker cohort. Lung cancer risk was expressed in terms of both the standardized mortality ratio (SMR) and the excess mortality rate (EMR). As in Canadian analyses, nonlinearity was assessed through a three parameter model containing both linear and negative exponential terms for dose. Dropping the negative-exponential dose-term lead to the standard suite of linear dose-response models, with and without intercept, used for comparative purposes. Analyses were undertaken by subcohort as there was strong evidence of confounding by year of initial hire, which largely explained the nonlinearity in the dose-response observed in Canadian analyses. Subcohort analyses based on initial employment, prior to 1940 or thereafter, showed that the nonlinearity in the dose-response was strongly influenced by date of initial hire. whether the cohort risk was measured by either the SMR or EMR, a nonlinear dose-response was evident only among workers hired prior to 1940. This, however, was strongly related to the artifactually low lung cancer mortality seen among workers hired between 1930 and 1939. Among workers hired after 1940, analyses showed that a linear dose-response provided a clearly superior fit. While analyses showed comparable goodness of fit when models were fitted to the SMR and EMR. Only those based on the EMR provided strong evidence of a dose-response. Overall, nonlinearity as observed in Canadian analyses was likely the result of several sources of bias not taken into account by Canadian investigators.

Reanalysis of dose-response data from the Iraqi methylmercury poisoning episode.

Applying a hockey stick parametric dose-response model to data on late or retarded development in Iraqi children exposed in utero to methylmercury, with mercury (Hg) exposure characterized by the peak Hg concentration in mothers' hair during pregnancy, Cox et al. calculated the "best statistical estimate" of the threshold for health effects as 10 ppm Hg in hair with a 95% range of uncertainty of between 0 and 13.6 ppm. A new application of the hockey stick model to the Iraqi data shows, however, that the statistical upper limit of the threshold based on the hockey stick model could be as high as 255 ppm. Furthermore, the maximum likelihood estimate of the threshold using a different parametric model is virtually zero. These and other analyses demonstrate that threshold estimates based on parametric models exhibit high statistical variability and model dependency, and are highly sensitive to the precise definition of an abnormal response. Consequently, they are not a reliable basis for setting a reference dose (RfD) for methylmercury. Benchmark analyses and statistical analyses useful for deriving NOAELs are also presented. We believe these latter analyses--particularly the benchmark analyses--generally form a sounder basis for determining RfDs than the type of hockey stick analysis presented by Cox et al. However, the acute nature of the exposures, as well as other limitations in the Iraqi data suggest that other data may be more appropriate for determining acceptable human exposures to methylmercury.

Unit risk estimates for airborne arsenic exposure: an updated view based on recent data from two copper smelter cohorts.

The current unit risk for airborne arsenic, 4.29 x 10(-3), was established by the EPA in 1984. Using updated results from a cohort mortality study on Tacoma smelter workers and recent findings from a cohort study of 3619 Swedish smelter workers, new unit risk estimates were developed for the respective cohorts. Methods were analogous to those used by the EPA in 1984, and all estimates were derived under an absolute risk model. A new unit risk 1.28 x 10(-3), was estimated for the Tacoma smelter cohort which was a factor of 5 less than the EPA's earlier estimate, and a direct result of radically revised exposure estimates. A unit risk of 0.89 x 10(-3) was estimated from the Swedish study. Pooling these new unit risk estimates with the EPA's earlier estimates from the Montana smelter cohort yielded a composite unit risk of 1.43 x 10(-3). Based on this estimate, the present unit risk may overestimate the effects of airborne arsenic by a factor of 3. A need to update the unit risk for airborne arsenic and the collateral IRIS database is evident from the results.

Case-control study of nasal cancer in workers employed in wood-related industries.

A case-control study of nasal cancer deaths in the states of Washington, Oregon, Mississippi, and North Carolina was undertaken to determine whether there was an excess of nasal cancer deaths occurring among workers in wood-related industries. This involved analysis of 536 cases of nasal cancer deaths occurring from 1962 to 1977, compared with 1,072 deaths matched for control. The study showed no overall excess of deaths from nasal cancer in wood-related industries, including furniture manufacturing. There was a statistically significant excess of deaths from nasal cancer occurring in lumber and wood products (risk ratio = 1.95, P less than .05); however, this was largely due to excess in these industries occurring in the states, of North Carolina and Mississippi. Summarizing the available evidence of this study, there seems to be no association between nasal cancer and industry/occupation normally identified with wood dust.

Epidemiologic evidence for an association between gasoline and kidney cancer.

A recent animal experiment suggests that gasoline exposure may be a cause of human kidney cancer. This is a literature review to see whether there is any epidemiologic support for these animal findings. Trends and geographic patterns in gasoline consumption and kidney cancer mortality are moderately supportive of a relationship, although this cannot be considered important evidence for a causal relationship. Most other ecological correlations are not supportive of a relationship. Eleven oil refinery populations and one population of petroleum products distribution workers have been studied. These studies taken as a group do not appear to support the notion of a relationship between gasoline exposure and kidney cancer. However, most were not designed or analyzed with this hypothesis in mind. An examination of these data which attempts to consider the ages of the populations studied provides some evidence of a small kidney cancer excess among older workers or among workers exposed for long periods. Because of the importance of gasoline and the potential for exposure by the public further study of exposed populations is needed.