An Ensemble Model of QSAR Tools for Regulatory Risk Assessment

Quantitative structure activity relationships (QSARs) are theoretical models that relate a quantitative measure of chemical structure to a physical property or a biological effect. QSAR predictions can be used for chemical risk assessment for protection of human and environmental health, which makes them interesting to regulators, especially in the absence of experimental data. For compatibility with regulatory use, QSAR models should be transparent, reproducible and optimized to minimize the number of false negatives. In silico QSAR tools are gaining wide acceptance as a faster alternative to otherwise time-consuming clinical and animal testing methods. However, different QSAR tools often make conflicting predictions for a given chemical and may also vary in their predictive performance across different chemical datasets. In a regulatory context, conflicting predictions raise interpretation, validation and adequacy concerns. To address these concerns, ensemble learning techniques in the machine learning paradigm can be used to integrate predictions from multiple tools. By leveraging various underlying QSAR algorithms and training datasets, the resulting consensus prediction should yield better overall predictive ability. We present a novel ensemble QSAR model using Bayesian classification. The model allows for varying a cut-off parameter that allows for a selection in the desirable trade-off between model sensitivity and specificity. The predictive performance of the ensemble model is compared with four in silico tools (Toxtree, Lazar, OECD Toolbox, and Danish QSAR) to predict carcinogenicity for a dataset of air toxins (332 chemicals) and a subset of the gold carcinogenic potency database (480 chemicals). Leave-one-out cross validation results show that the ensemble model achieves the best trade-off between sensitivity and specificity (accuracy: 83.8 % and 80.4 %, and balanced accuracy: 80.6 % and 80.8 %) and highest inter-rater agreement [kappa (κ): 0.63 and 0.62] for both the datasets. The ROC curves demonstrate the utility of the cut-off feature in the predictive ability of the ensemble model. This feature provides an additional control to the regulators in grading a chemical based on the severity of the toxic endpoint under study

Regulating Carcinogens in Food: A Legislator\u27s Guide to the Food Safety Provisions of the Federal Food, Drug, and Cosmetic Act

On March 9, 1977, the Food and Drug Administration (FDA) announced that a study in laboratory rats conducted by the Canadian government confirmed that saccharin is an animal carcinogen. For this reason, the agency stated, the sweetener must be banned from human food. The studies which Congress mandated, to be accompanied by the recommendations of the Secretary of HEW, are likely to generate a fundamental reexamination of the nation\u27s current food safety policies. This Article attempts to aid this inquiry by explaining the requirements of the present law. The Article describes the several statutory provisions that govern the regulation of food constituents and analyzes the FDA\u27s implementation of them. Its primary objective is to provide a common starting place for discussion of the contours of future policy. A subsequent article will examine in detail various approaches to regulating risks posed by food and recommend specific reforms of the present law

Reducing Diet-Induced Cancer Through Federal Regulation: Opportunities and Obstacles

For more than a decade, federal health regulatory agencies have devoted major attention to controlling human exposure to substances believed capable of causing cancer. These efforts have evoked a broad spectrum of criticism; government has been accused of both indolence in the face of an incipient epidemic\u27 and reckless distortion of science to support restrictions on substances that present only trivial risks. A central object of regulatory concern has been the safety of the food supply. At least since the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act),\u27with its famous Delaney Clause, the Food and Drug Administration (FDA) has sought, with mixed success, to identify food constituents that pose cancer risks and to eliminate them from food. The Environmental Protection Agency (EPA), which is responsible for setting permissible pesticide levels in food, has displayed similar concern for the elimination of carcinogenic residues in foods that comprise important parts of the American diet. I do not propose here to evaluate the success of the FDA\u27s and the EPA\u27s efforts to prevent the addition of hazardous chemicals to the food supply. While that is certainly an important issue, this Article explores the potentially greater challenges to regulation presented by recent assessments suggesting highly significant associations be-tween traditional foods and cancer incidence. This Article does not identify all the relevant issues or exhaust analysis of those it does address; the objective is to sketch the broad contours of future debate

FDA\u27s Implementation of the Delaney Clause: Repudiation of Congressional Choice or Reasoned Adaptation to Scientific Progress?

The Delaney Clause, the most famous federal health statute, bars Food and Drug Administration (FDA) approval of any carcinogenic food additive. In an era when scholars and politicians are again voicing concern about the propensity of legislatures to delegate broad power to administrators, the Delaney Clause is an exceptional illustration of Congress\u27s capacity to enact specific laws. The Clause seems to express the unequivocal judgment that consumers should not be exposed to food ingredients shown to cause cancer, regardless of the benefits the ingredients might provide or the magnitude of the risk that they might present. Like many extreme policies, the Delaney Clause has proved increasingly difficult to administer