The effect of confounding variables in studies of lead exposure and IQ.

Methods proposed to address confounding variables frequently do not adequately distinguish confounding from covariation. A confounder is a variable that correlates both with the outcome and the major exposure variable. Accurate treatment of confounding is crucial to low dose extrapolation of the effects of chemical exposures based on epidemiology studies. This study explores the limitations of current regression models in extrapolation to the low dose region of the dose-response curve due to the existence of unrecognized and uncontrolled confounding, using epidemiological data for lead. Based on the reported data in analyses by Lanphear and colleagues and Crump and colleagues, and drawing on other studies, Wilson and Wilson considered maternal IQ, HOME score, SES, parental education, birthweight, smoking, and race as characteristic variables which may have interaction effects. This analysis identifies confounding variables based on the seven longitudinal cohorts in analyses conducted by Lanphear and colleagues and by Crump and colleagues and confirms maternal IQ, HOME score, maternal education and maternal marital status at birth are "Highly Likely" confounders, while race is a "Likely" confounder. The cohort data were reanalyzed using the methods presented by Crump and colleagues while also considering the interaction among the identified confounding variables. This analysis determined that confounders influence IQ estimates in a quantifiable way that may exceed or at least obscure previously-reported effects of blood lead on IQ with blood lead levels below 5 µg/dL; however, limitations in the datasets make predictions of the low dose dose-response analysis questionable.

A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling-The importance of homeostatic control for an essential metal.

A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10µg/m3) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to "convert" an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls.

Evaluating the association between menthol cigarette use and the likelihood of being a former versus current smoker.

Menthol in cigarettes has been examined for its potential to affect smoking dependence, measured primarily as number of cigarettes smoked per day and time to first cigarette after waking; the ability to quit smoking constitutes an additional measure of dependence. Successful quitting among menthol compared to non-menthol cigarette smokers is difficult to determine from the literature, due in part to the various definitions of quitting used by researchers. Nevertheless, intervention and follow-up studies of smoking cessation treatments generally indicate no differences in quitting success among menthol compared to non-menthol smokers, while cross-sectional studies suggest some differences within race/ethnicity groups. The association between menthol cigarette use and likelihood of being a former versus current smoker was examined based on data from the National Health Interview Survey and Tobacco Use Supplement to the Current Population Survey. Analyses stratified by race/ethnicity and limited to smokers who had quit at least one year prior to survey participation provided inconsistent results with regard to menthol cigarette use and quitting, both within surveys (i.e., comparing race/ethnicity groups) and between surveys (i.e., same race/ethnicity group across surveys). Evidence suggesting the existence or direction of an association between menthol in cigarettes and quitting depended on the data source.